Azabicyclo (3.1.0) Hexane Derivatives Useful As Modulators Of Dopamine D3 Receptors

ABSTRACT

The present invention relates to novel compounds of formula (I) or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein
         G is selected from a group consisting of: phenyl, pyridyl, benzothiazolyl, indazolyl;   p is an integer ranging from 0 to 5;   R 1  is independently selected from a group consisting of: halogen, hydroxy, cyano, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkoxy, C 1-4 alkanoyl; or corresponds to a group R 5 ;   R 2  is hydrogen or C 1-4 alkyl;   R 3  is C 1-4 alkyl;   R 4  is hydrogen, or a phenyl group, a heterocyclyl group, a 5- or 6-membered heteroaromatic group, or a 8- to 11-membered bicyclic group, any of which groups is optionally substituted by 1, 2, 3 or 4 substituents selected from the group consisting of: halogen, cyano, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkanoyl;   R 5  is a moiety selected from the group consisting of: isoxazolyl, —CH 2 —N-pyrrolyl, 1,1-dioxido-2-isothiazolidinyl, thienyl, thiazolyl, pyridyl, 2-pyrrolidinonyl, and such a group is optionally substituted by one or two substituents selected from: halogen, cyano, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkanoyl;
 
and when R 1  is chlorine and p is 1, such R 1  is not present in the ortho position with respect to the linking bond to the rest of the molecule; and when R 1  corresponds to R 5 , p is 1;
 
processes for their preparation, intermediates used in these processes, pharmaceutical compositions containing them and their use in therapy, as modulators of dopamine D 3  receptors, e.g. to treat drug dependency or as antipsychotic agents.

The present invention relates to novel compounds, processes for theirpreparation, intermediates used in these processes, pharmaceuticalcompositions containing them and their use in therapy, as modulators ofdopamine D₃ receptors.

WO 2002/40471 (SmithKline Beecham) discloses certain benzazepinecompounds having activity at the dopamine D₃ receptor.

A new class of compounds which have affinity for dopamine receptors, inparticular the dopamine D₃ receptor has been found. These compounds havepotential in the treatment of conditions wherein modulation, especiallyantagonism/inhibition, of the D₃ receptor is beneficial, e.g. to treatdrug dependency or as antipsychotic agents.

The present invention provides a compound of formula (I) or a saltthereof:

wherein

-   -   G is selected from a group consisting of: phenyl, pyridyl,        benzothiazolyl, indazolyl;    -   p is an integer ranging from 0 to 5;    -   R₁ is independently selected from a group consisting of:        halogen, hydroxy, cyano, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy,        haloC₁₋₄alkoxy, C₁₋₄alkanoyl; or corresponds to a group R₅;    -   R₂ is hydrogen or C₁₋₄alkyl;    -   R₃ is C₁₋₄alkyl;    -   R₄ is hydrogen, or a phenyl group, a heterocyclyl group, a 5- or        6-membered heteroaromatic group, or a 8- to 11-membered bicyclic        group, any of which groups is optionally substituted by 1, 2, 3        or 4 substituents selected from the group consisting of:        halogen, cyano, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy,        C₁₋₄alkanoyl;    -   R₅ is a moiety selected from the group consisting of:        isoxazolyl, —CH₂—N-pyrrolyl, 1,1-dioxido-2-isothiazolidinyl,        thienyl, thiazolyl, pyridyl, 2-pyrrolidinonyl, and such a group        is optionally substituted by one or two substituents selected        from: halogen, cyano, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy,        C₁₋₄alkanoyl;        and when R₁ is chlorine and p is 1, such R₁ is not present in        the ortho position with respect to the linking bond to the rest        of the molecule; and when R₁ corresponds to R₅, p is 1.

Because of the presence of the fused cyclopropane compounds of formula(I) are believed to have a “cis” disposition of the substituents (bothgroups linked to the bicyclic ring system are on the same face of thisbicyclic ring system).

In another embodiment of the present invention compounds of formula (I)′are provided which correspond to the compounds of formula (I) having“cis” disposition, represented by the bold highlight of the bonds

wherein G, p, R₁, R₂, R₃, R₄, and R₅ are defined as above for compoundsof formula (I).

It will be appreciated that compounds of formula (I)′ possess at leasttwo chiral centres, namely at position 1 and 5 in the3-azabicyclo[3.1.0]hexane portion of the molecule. Because of the fixedcis disposition, the compounds may exist in two stereoisomers which areenantiomers with respect to the chiral centres in the cyclopropane. Itwill also be appreciated, in common with most biologically activemolecules that the level of biological activity may vary between theindividual stereoisomers of a given molecule. It is intended that thescope of the invention includes all individual stereoisomers(diastereoisomers and enantiomers) and all mixtures thereof, includingbut not limited to racemic mixtures, which demonstrate appropriatebiological activity with reference to the procedures described herein.

In compounds of formula (I)′ there are at least two chiral centres,which are located in the cyclopropane portion, as depicted below (thebold highlight of the bonds means the “cis” configuration):

-   -   when G is a 2-pyridyl derivative the configuration becomes        (1R,5R) due to different Cahn-Ingold-Prelog nomenclature        priorities

In a further embodiment of the present invention compounds of formula(IA) are provided that correspond to stereochemical isomers of compoundsof formula (I)′, enriched in configuration (1S,5R) or (1R,5R)

wherein G, p, R₁, R₂, R₃, R₄, and R₅ are defined as above for compoundsof formula (I)′ or a pharmaceutically acceptable salt thereof.

It is intended in the context of the present invention thatstereochemical isomers enriched in configuration (1S,5R) or (1R,5R) offormula (IA) correspond in one embodiment to at least 90% e.e. Inanother embodiment the isomers correspond to at least 95% e.e. Inanother embodiment the isomers correspond to at least 99% e.e.

In another embodiment of the present invention the stereochemicalisomers enriched in configuration (1R,5S) are provided:

-   5-[5-({3-[(1R,5S)-1-(4-Methoxyphenyl)-3-azabicyclo[3.1.0]hex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazol-3-yl]-2-methylquinoline,    Enantiomer 2;-   5-[5-({3-[(1R,5S)-1-(4-Bromophenyl)-3-azabicyclo[3.1.0]hex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazol-3-yl]-2-methylquinoline,    Enantiomer 1;-   5-[5-({3-[(1R,5S)-1-(4-tert-Butylphenyl)-3-azabicyclo[3.1.0]hex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazol-3-yl]-2-methylquinoline,    Enantiomer 1;-   (1R,5S)-3-(3-{[4-Methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[3-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane,    Enantiomer 2;-   (1R,5S)-1-(3-Chlorophenyl)-5-methyl-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane,    Enantiomer 2;-   1-[5-[(1R,5S)-3-{[4-Methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}-propyl)-3-azabicyclo[3.1.0]hex-1-yl]-2-(methyloxy)phenyl]-1-propanone,    Enantiomer 2;-   2-Methyl-5-[(1R,5S)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]-1,3-benzothiazole,    Enantiomer 2; or a pharmaceutically acceptable salt thereof.

The term “5- or 6-membered heteroaromatic group” refers to a monocyclic5- or 6-membered heterocyclic group containing 1, 2, 3 or 4 heteroatoms,for example from 1 to 3 heteroatoms, selected from O, N and S. When thegroup contains 2-4 heteroatoms, one may be selected from O, N and S andthe remaining heteroatoms may be N. Examples of 5 and 6-memberedheteroaromatic groups include pyrrolyl, imidazolyl, pyrazolyl, oxazolyl,isoxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, furyl, thienyl,thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazinyl, pyrimidinyland pyrazinyl.

The term “C₁₋₄alkyl” refers to an alkyl group having from one to fourcarbon atoms, in all isomeric forms, such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. The term“n-C₁₋₄alkyl” refers to the unbranched alkyls as defined above.

The term “C₁₋₄alkoxy” refers to a straight chain or branched chainalkoxy (or “alkyloxy”) group having from one to four carbon atoms, suchas methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxyand tert-butoxy.

The term “halogen” and its abbreviation “halo” refer to fluorine (F),chlorine (CI), bromine (Br) or iodine (I). Where the term “halo” is usedbefore another group, it indicates that the group is substituted by one,two or three halogen atoms. For example, “haloC₁₋₄alkyl” refers togroups such as trifluoromethyl, bromoethyl, trifluoropropyl, and othergroups derived from C₁₋₄alkyl groups as defined above; and the term“haloC₁₋₄alkoxy” refers to groups such as trifluoromethoxy, bromoethoxy,trifluoropropoxy, and other groups derived from C₁₋₄alkoxy groups asdefined above.

The term “8- to 11-membered bicyclic group” refers to a bicyclic ringsystem containing a total of 8, 9, 10 or 11 carbon atoms, wherein 1, 2,3 or 4 or 5 of the carbon atoms are optionally replaced by a heteroatomindependently selected from O, S and N. The term includes bicyclicsystems wherein both rings are aromatic, as well as bicyclic ringsystems wherein one of the rings is partially or fully saturated.Examples of 8- to 11-membered bicyclic groups wherein both rings arearomatic include indenyl, naphthyl and azulenyl.

Examples of 8- to 11-membered bicyclic groups having 1, 2, 3, 4 or 5heteroatoms, in which both rings are aromatic, include:6H-thieno[2,3-b]pyrrolyl, imidazo[2,1-b][1,3]thiazolyl,imidazo[5,1-b][1,3]thiazolyl, [1,3]thiazolo[3,2-b][1,2,4]triazolyl,indolyl, isoindolyl, indazolyl, benzimidazolyl e.g. benzimidazol-2-yl,benzoxazolyl e.g. benzoxazol-2-yl, benzisoxazolyl, benzothiazolyl,benzisothiazolyl, benzothienyl, benzofuranyl, naphthridinyl, quinolyl,quinoxalinyl, quinazolinyl, cinnolinyl and isoquinolyl. Examples of 8-to 11-membered bicyclic groups having 1, 2, 3, 4 or 5 heteroatoms, inwhich one of the rings is partially or fully saturated includesdihydrobenzofuranyl, indanyl, tetrahydronaphthyl, indolinyl,isoindolinyl, tetrahydroisoquinolinyl, tetrahydroquinolyl, benzoxazinyland benzoazepinyl.

The term “heterocyclyl” refers to a 5 or 6-membered monocyclic or 8 to11-membered bicyclic group wherein 1, 2, 3, 4 or 5 of the carbon atomsare replaced by a heteroatom independently selected from O, S and N andwhich is partially or fully saturated. Examples of “heterocyclyl” whichare fully saturated 5 or 6-membered monocyclic rings includepyrrolidinyl, imidazolidinyl, pyrazolidinyl, isothiazolyl, thiazolyl,tetrahydrofuranyl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl,thiomorpholinyl, tetrahydrothienyl, dioxanyl, tetrahydro-2H-pyranyl anddithianyl. Examples of “heterocyclyl” groups which are partiallysaturated 5 or 6-membered monocyclic rings include oxazolinyl,isoaxazolinyl, imidazolinyl, pyrazolinyl, 1,2,3,6-tetrahydropyridyl and3,6-dihydro-2H-pyranyl. Examples of “heterocyclyl” groups which arefully saturated 8 to 11-membered bicyclic rings includedecahydroquinolinyl, octahydro-2H-1,4-benzoxazinyl andoctahydro-1H-cyclopenta-[b]pyridinyl. Examples of “heterocyclyl” groupswhich are partially saturated 8 to 11-membered bicyclic rings include2,3-dihydro-1H-indolyl, 1,2,3,4-tetrahydroquinolinyl,1,2,3,4-tetrahydroisoquinolinyl and2,3,4,5-tetrahydro-1H-3-benzazepinyl.

Any of these groups may be attached to the rest of the molecule at anysuitable position.

As used herein, the term “salt” refers to any salt of a compoundaccording to the present invention prepared from an inorganic or organicacid or base, quaternary ammonium salts and internally formed salts.Physiologically acceptable salts are particularly suitable for medicalapplications because of their greater aqueous solubility relative to theparent compounds. Such salts must clearly have a physiologicallyacceptable anion or cation. Suitably physiologically acceptable salts ofthe compounds of the present invention include acid addition saltsformed with inorganic acids such as hydrochloric, hydrobromic,hydroiodic, phosphoric, metaphosphoric, nitric and sulfuric acids, andwith organic acids, such as tartaric, acetic, trifluoroacetic, citric,malic, lactic, fumaric, benzoic, formic, propionic, glycolic, gluconic,maleic, succinic, camphorsulfuric, isothionic, mucic, gentisic,isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic,anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic),methanesulfonic, ethanesulfonic, pantothenic, stearic, sulfinilic,alginic, galacturonic and arylsulfonic, for example benzenesulfonic andp-toluenesulfonic, acids; base addition salts formed with alkali metalsand alkaline earth metals and organic bases such asN,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumaine (N-methylglucamine), lysine and procaine;and internally formed salts. Salts having a non-physiologicallyacceptable anion or cation are within the scope of the invention asuseful intermediates for the preparation of physiologically acceptablesalts and/or for use in non-therapeutic, for example, in vitro,situations.

In one embodiment, R₁ is halogen, cyano, acetyl, trifluoromethyl,trifluoromethoxy.

In one embodiment, R₂ is hydrogen. In another embodiment R₂ is C₁₋₄alkyl (e.g. methyl).

In one embodiment, R₅ is a group selected from: isoxazolyl,2-pyrrolidinonyl, 1,1-dioxido-2-isothiazolidinyl which is optionallysubstituted by one or two substituents selected from: halogen, cyano,C₁₋₂alkyl (e.g. methyl), haloC₁₋₂alkyl (e.g. trifluoromethyl),C₁₋₂alkoxy (e.g. methoxy), C₁₋₃alkanoyl (e.g. acetyl).

Suitably, R₁ is bromo, fluoro, trifluoromethoxy, cyano, hydroxy, chloro,methoxy, tert-butyl, trifluoromethyl.

Suitably, R₅ is isoxazolyl, 2-pyrrolidinonyl, —CH₂—N-pyrrolyl,1,1-dioxido-2-isothiazolidinyl, 2-thienyl, 2-pyridyl, 2-thiazolyl.

In one embodiment, p is 1 or 2.

In another embodiment p is 0.

In one embodiment, R₄ may be optionally substituted phenyl (e.g. phenyl,4-trifluoromethyl-phenyl, 3,4-difluorophenyl), an optionally substitutedbicyclic group such as quinolinyl (e.g. 2-methylquinoline,8-fluoro-2-methylquinoline), an optionally substituted pyranyl (e.g.4-tetrahydro-2H-pyranyl), an optionally substituted pyridinyl (e.g.3-methyl-2-pyridinyl, 2-methyl-3-pyridinyl, 3-pyridinyl,2-methyl-6-trifluoromethyl-3-pyridinyl), an optionally substitutedpyrazolyl (e.g. 5-chloro-1-methyl-1H-pyrazol-4-yl,1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl1,5-dimethyl-1H-pyrazoly-4-yl), an optionally substituted pyrimidyl(e.g. 5-pyrimidinyl), an optionally substituted pyridazinyl (e.g.4-pyridazinyl), an optionally substituted pyrazinyl (e.g.5-methyl-2-pyrazinyl), an optionally substituted furanyl (e.g.3-methyl-2-furanyl, 2,5-dimethyl-3-furanyl), an optionally substitutedthienyl (e.g. 5-chloro-2-thienyl), an optionally substituted oxazolyl(e.g. 4-methyl-1,3-oxazol-5-yl,2-methyl-5-trifluoromethyl-1,3-oxazol-4-yl), an optionally substitutedisoxazolyl (e.g. 3-methyl-5-isoxazolyl), an optionally substitutedthiazolyl (e.g. 2,4-dimethyl-1,3-thiazol-5-yl), an optionallysubstituted triazolyl (e.g. 1-methyl-1H-1,2,3-triazol-4-yl).

In one embodiment, R₃ is methyl.

In one embodiment, a compound of formula (IB) or a salt thereof isprovided, wherein R₁, P, R₃ and R₄ are as defined for formula (I):

In Formula (IB), in one embodiment, R₃ is methyl. R₄ may be phenyl,heterocyclyl, 5- or 6-membered heteroaromatic group or a 9- to11-membered bicyclic group, any of which is optionally substituted by 1,2, 3 or 4 substituents selected from the group consisting of: halogen,hydroxy, oxo, cyano, nitro, C₁₋₄alkyl, fluoroC₁₋₄alkyl, C₁₋₄alkoxy,fluoroC₁₋₄alkoxy, C₁₋₄alkanoyl; and when R₁ is chlorine and p is 1, suchR₁ is not present in the ortho position with respect to the linking bondto the rest of the molecule.

Examples of R₄ include an optionally substituted phenyl (e.g. phenyl,4-trifluoromethyl-phenyl, 3,4-difluorophenyl), an optionally substitutedbicyclic group such as quinolinyl (e.g. 2-methylquinoline,8-fluoro-2-methylquinoline), an optionally substituted pyranyl (e.g.4-tetrahydro-2H-pyranyl), an optionally substituted pyridinyl (e.g.3-methyl-2-pyridinyl, 2-methyl-3-pyridinyl, 3-pyridinyl,2-methyl-6-trifluoromethyl-3-pyridinyl), an optionally substitutedpyrazolyl (e.g. 5-chloro-1-methyl-1H-pyrazol-4-yl,1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl1,5-dimethyl-1H-pyrazoly-4-yl), an optionally substituted pyrimidyl(e.g. 5-pyrimidinyl), an optionally substituted pyridazinyl (e.g.4-pyridazinyl), an optionally substituted pyrazinyl (e.g.5-methyl-2-pyrazinyl), an optionally substituted furanyl (e.g.3-methyl-2-furanyl, 2,5-dimethyl-3-furanyl), an optionally substitutedthienyl (e.g. 5-chloro-2-thienyl), an optionally substituted oxazolyl(e.g. 4-methyl-1,3-oxazol-5-yl,2-methyl-5-trifluoromethyl-1,3-oxazol-4-yl), an optionally substitutedisoxazolyl (e.g. 3-methyl-5-isoxazolyl), an optionally substitutedthiazolyl (e.g. 2,4-dimethyl-1,3-thiazol-5-yl), an optionallysubstituted triazolyl (e.g. 1-methyl-1H-1,2,3-triazol-4-yl).

In another embodiment, a compound of formula (IC) or a salt thereof isprovided, wherein R₁, p, R₃ and R₄ are as defined for formula (I):

In Formula (IC), in one embodiment, R₃ is methyl. R₄ may be phenyl,heterocyclyl, 5- or 6-membered heteroaromatic group or a 9- to11-membered bicyclic group, any of which is optionally substituted by 1,2, 3 or 4 substituents selected from the group consisting of: halogen,hydroxy, oxo, cyano, nitro, C₁₋₄alkyl, fluoroC₁₋₄alkyl, C₁₋₄alkoxy,fluoroC₁₋₄alkoxy, C₁₋₄alkanoyl; and when R₁ is chlorine and p is 1, suchR₁ is not present in the ortho position with respect to the linking bondto the rest of the molecule. Examples of R₄ include those definedpreviously for compounds (IB).

In another embodiment, a compound of formula (ID) or a salt thereof isprovided, wherein R₁, p, R₃ and R₄ are as defined for formula (I):

In Formula (ID), in one embodiment, R₃ is methyl. R₄ may be phenyl,heterocyclyl, 5- or 6-membered heteroaromatic group or a 9- to11-membered bicyclic group, any of which is optionally substituted by 1,2, 3 or 4 substituents selected from the group consisting of: halogen,hydroxy, oxo, cyano, nitro, C₁₋₄alkyl, fluoroC₁₋₄alkyl, C₁₋₄alkoxy,fluoroC₁₋₄alkoxy, C₁₋₄alkanoyl; and when R₁ is chlorine and p is 1, suchR₁ is not present in the ortho position with respect to the linking bondto the rest of the molecule.

Examples of R₄ include those defined previously for compounds (IB).

In another embodiment, a compound of formula (IE) or a salt thereof isprovided, wherein G is 2-pyridyl or 3-pyridyl and R₁, p, R₃ and R₄ areas defined for formula (I):

In Formula (IE), in one embodiment, G corresponds to 2-pyridyl(Compounds (IE₁)) and in another embodiment to 3-pyridyl (Compounds(IE₂)), as illustrated below:

In Formulae (IE), (IE₁) and (IE₂), in one embodiment, R₃ is methyl. R₄may be phenyl, heterocyclyl, 5- or 6-membered heteroaromatic group or a9- to 11-membered bicyclic group, any of which is optionally substitutedby 1, 2, 3 or 4 substituents selected from the group consisting of:halogen, hydroxy, oxo, cyano, nitro, C₁₋₄alkyl, fluoroC₁₋₄alkyl,C₁₋₄alkoxy, fluoroC₁₋₄alkoxy, C₁₋₄alkanoyl; and when R₁ is chlorine andp is 1, such R₁ is not present in the ortho position with respect to thelinking bond to the rest of the molecule.

Examples of R₄ include those defined previously for compounds (IB).

In another embodiment, a compound of formula (IF) or a salt thereof isprovided, wherein R₁, p, R₃ and R₄ are as defined for formula (I):

In Formula (IF), in one embodiment, R₃ is methyl. R₄ may be phenyl,heterocyclyl, 5- or 6-membered heteroaromatic group or a 9- to11-membered bicyclic group, any of which is optionally substituted by 1,2, 3 or 4 substituents selected from the group consisting of: halogen,hydroxy, oxo, cyano, nitro, C₁₋₄alkyl, fluoroC₁₋₄alkyl, C₁₋₄alkoxy,fluoroC₁₋₄alkoxy, C₁₋₄alkanoyl; and when R₁ is chlorine and p is 1, suchR₁ is not present in the ortho position with respect to the linking bondto the rest of the molecule.

Examples of R₄ include those defined previously for compounds (IB).

The strategy for determining the absolute configuration of the compoundsof the present invention comprised as a first step the preparation ofthe chiral intermediate,(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane,

(preparation 18), by using (S)-(+) acetyl mandelic acid as resolvingagent.

In the literature the absolute configuration of a series of compoundssimilar to this chiral intermediate is known, see J. Med Chem 1981,24(5), 481-90. For some compounds disclosed in the reference theabsolute configuration was proved by single crystal X-ray analysis.

Among them, 1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane wasdisclosed.

The absolute configuration of the optical isomers of the compounds ofthe present invention was assigned using comparative VCD (vibrationalcircular dichroism) and OR (optical rotation) analyses.

The configuration of(1S,5R)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane was assigned bycomparing its experimental VCD spectrum and observed specific rotationto ab initio derived calculated data for(1S,5R)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane (seePreparation 48) as the reference sample.

The assignment of the absolute configuration of the title compound wasconfirmed by a single crystal X-ray structure obtained from a crystal of(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane,(S)-(+)-mandelic acid salt. Both the analysis based on the knownconfiguration of the (S)-(+)-mandelic acid and on the basis of anomalousdispersion effects confirmed the assignment of the title compound asbeing (1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane.

For those compounds which were subjected to detailed analysis (VCD; ORincluded in the experimental details) a common trend was recognisedbetween absolute configuration of the 3-azabicyclo[3.1.0]hexane moietyand measured binding activity at the dopamine D3 receptor for each pairof enantiomers. For the remainder of the compounds of the presentinvention, where stereoisomers were evaluated separately, absoluteconfiguration was assigned based on a reasonable assumption by a skilledperson in the art, i.e. absolute configuration was then assigned basedon measured binding activity at the dopamine D3 receptor for bothenantiomers and comparison with the data of those compounds which weresubjected to detailed analysis.

Chiral molecules exhibit vibrational circular dichroism (VCD).Vibrational circular dichroism (VCD) is the differential interaction ofa chiral molecule with left and right circularly polarized infraredradiation during vibrational excitation.

The VCD spectrum of a chiral molecule is dependent on itsthree-dimensional structure.

Most importantly, the VCD spectrum of a chiral molecule is a sensitivefunction of its absolute configuration and, in the case of flexiblemolecules, of its conformation. In principle, therefore, VCD permits thedetermination of the structure of a chiral molecule. VCD spectra werefirst measured in the 1970s. Subsequently, VCD instrumentation hasdeveloped enormously in spectral range and in sensitivity. Currently,VCD spectra of liquids and solutions can be measured over the majorityof the fundamental infrared (IR) spectral range (v≧650 cm-1) with highsensitivity at acceptable resolution (1-5 cm-1) using both dispersiveand Fourier Transform (FT) VCD instrumentation. Very recently,commercial FT VCD instrumentation has become available, greatlyenhancing the accessibility of VCD spectra.

The use of VCD as a reliable method for the determination of absoluteconfiguration of chiral molecules is now well established (see forexample Shah R D. et al., Curr Opin Drug Disc Dev 2001; 4:764-774;Freedman T B, et al., Helv Chim Acta 2002; 85:1160-1165; Dyatkin A B, etal. Chirality 2002; 14:215-219; Solladié-Cavallo A, Balaz M et al.,Tetrahedron Assym 2001; 12:2605-2611; Nafie L A, et al. Circulardichroism, principles and applications, 2nd ed. New York: John Wiley &Sons; 2000. p 97-131; Nafie L A, et al. in: Yan B, Gremlish H-U,editors. Infrared and Raman spectroscopy of biological materials. NewYork: Marcel Dekker; 2001. p 15-54; Polavarapu P L, et al., J Anal Chem2000; 366:727-734; Stephens P J, et al., Chirality 2000; 12:172-179;Solladié-Cavallo A, et al., Eur J Org Chem 2002: 1788-1796).

The method entails comparison of observed IR and VCD spectra withcalculations of the spectra for a specific configuration and providesinformation both on the absolute configuration and on the solutionconformation.

Given an experimental spectrum of a chiral molecule whose absoluteconfiguration and/or conformation are unknown and to be determined, thegeneral procedure is as follows: 1) all possible structures are defined;2) the spectra of these structures are predicted; and 3) predictedspectra are compared to the experimental spectrum. The correct structurewill give a spectrum in agreement with experiment; incorrect structureswill give spectra in disagreement with experiment.

VCD spectra are always measured simultaneously with vibrationalunpolarized absorption spectra (“infrared (IR) spectra”) and the twovibrational spectra together provide more information than does the VCDspectrum alone. In addition, vibrational unpolarized absorption spectraare automatically predicted simultaneously with VCD spectra.

For ab initio assignments, VCD and unpolarized IR spectra werecalculated using the Gaussian 98 software package.

When chiral organic molecules are synthesized (or, if natural products,isolated) their optical rotations are routinely measured at onefrequency or at a small number of discrete frequencies in thevisible—near ultraviolet spectral region. Most commonly, the specificrotation at one frequency, that of the sodium D line, [α]_(D), ismeasured. The frequencies used lie below the threshold for electronicabsorption, i.e., they are in the “transparent” spectral region. Opticalrotation is a reflection of the enantiomeric excess (ee) of the sampleand of the absolute configuration (AC) of the predominant enantiomer.

When the optical rotation at a given frequency for 100% ee is available,the measured optical rotation at the same frequency enables the sampleee to be determined.

The determination of ee is the predominant application of discretefrequency, transparent spectral region optical rotations. In principle,the AC of the predominant enantiomer, if unknown, can also bedetermined. However, the determination of AC from optical rotationrequires an algorithm which reliably predicts the optical rotations ofmolecules of known AC and a number of methodologies have been proposedfor predicting discrete frequency, transparent spectral region opticalrotations (Eliel E L, Wilen S H. Stereochemistry of organic compounds.New York: John Wiley & Sons; 1994. Chapter 13).

Very recently, developments in ab initio Density Functional Theory (DFT)have radically improved the accuracy of optical rotation calculation. Asa result, for the first time it has become possible to routinely obtainACs from optical rotations.

For ab initio OR assignments, the Dalton Quantum Chemistry Program wasused.

Further embodiments of the present invention are compounds of formula(IB)′, (IC)′, (ID)′, and (IF)′ which, respectively, correspond to thestereochemical isomers of compounds of formula (IB), (IC), (ID) and (IF)as defined above enriched in configuration (1S,5R).

Compounds of formula (IE)′ correspond to the stereochemical isomers ofcompounds of formula (IE) as above defined, enriched in configuration(1R,5R) or (1R,5S) depending on the presence of a 2-pyridine ring.

In one embodiment, a stereochemical isomer enriched in the (1S,5R)configuration of formula (IB)′ or a salt thereof is provided, whereinR₁, p, R₃ and R₄ are as defined for formula (I):

In Formula (IB)′, in one embodiment, R₃ is methyl. R₄ may be phenyl,heterocyclyl, 5- or 6-membered heteroaromatic group or a 9- to11-membered bicyclic group, any of which is optionally substituted by 1,2, 3 or 4 substituents selected from the group consisting of: halogen,hydroxy, oxo, cyano, nitro, C₁₋₄alkyl, fluoroC₁₋₄alkyl, C₁₋₄alkoxy,fluoroC₁₋₄alkoxy, C₁₋₄alkanoyl; and when R₁ is chlorine and p is 1, suchR₁ is not present in the ortho position with respect to the linking bondto the rest of the molecule.

Examples of R₄ include optionally substituted phenyl (e.g. phenyl,4-trifluoromethyl-phenyl, 3,4-difluorophenyl), an optionally substitutedbicyclic group such as quinolinyl (e.g. 2-methylquinoline,8-fluoro-2-methylquinoline), an optionally substituted pyranyl (e.g.4-tetrahydro-2H-pyranyl), an optionally substituted pyridinyl (e.g.3-methyl-2-pyridinyl, 2-methyl-3-pyridinyl, 3-pyridinyl,2-methyl-6-trifluoromethyl-3-pyridinyl), an optionally substitutedpyrazolyl (e.g. 5-chloro-1-methyl-1H-pyrazol-4-yl,1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl1,5-dimethyl-1H-pyrazoly-4-yl), an optionally substituted pyrimidyl(e.g. 5-pyrimidinyl), an optionally substituted pyridazinyl (e.g.4-pyridazinyl), an optionally substituted pyrazinyl (e.g.5-methyl-2-pyrazinyl), an optionally substituted furanyl (e.g.3-methyl-2-furanyl, 2,5-dimethyl-3-furanyl), an optionally substitutedthienyl (e.g. 5-chloro-2-thienyl), an optionally substituted oxazolyl(e.g. 4-methyl-1,3-oxazol-5-yl,2-methyl-5-trifluoromethyl-1,3-oxazol-4-yl), an optionally substitutedisoxazolyl (e.g. 3-methyl-5-isoxazolyl), an optionally substitutedthiazolyl (e.g. 2,4-dimethyl-1,3-thiazol-5-yl), an optionallysubstituted triazolyl (e.g. 1-methyl-1H-1,2,3-triazol-4-yl).

In another embodiment, a stereochemical isomer enriched in the (1S,5R)configuration of formula (IC)′ or a salt thereof is provided, whereinR₁, p, R₃ and R₄ are as defined for formula (I):

In Formula (IC), in one embodiment, R₃ is methyl. R₄ may be phenyl,heterocyclyl, 5- or 6-membered heteroaromatic group or a 9- to11-membered bicyclic group, any of which is optionally substituted by 1,2, 3 or 4 substituents selected from the group consisting of: halogen,hydroxy, oxo, cyano, nitro, C₁₋₄alkyl, fluoroC₁₋₄alkyl, C₁₋₄alkoxy,fluoroC₁₋₄alkoxy, C₁₋₄alkanoyl; and when R₁ is chlorine and p is 1, suchR₁ is not present in the ortho position with respect to the linking bondto the rest of the molecule. Examples of R₄ include those definedpreviously for compounds (IB)′.

In another embodiment, a stereochemical isomer enriched in the (1S,5R)configuration of formula (ID)′ or a salt thereof is provided, whereinR₁, p, R₃ and R₄ are as defined for formula (I):

In Formula (ID)′, in one embodiment, R₃ is methyl. R₄ may be phenyl,heterocyclyl, 5- or 6-membered heteroaromatic group or a 9- to11-membered bicyclic group, any of which is optionally substituted by 1,2, 3 or 4 substituents selected from the group consisting of: halogen,hydroxy, oxo, cyano, nitro, C₁₋₄alkyl, fluoroC₁₋₄alkyl, C₁₋₄alkoxy,fluoroC₁₋₄alkoxy, C₁₋₄alkanoyl; and when R₁ is chlorine and p is 1, suchR₁ is not present in the ortho position with respect to the linking bondto the rest of the molecule. Examples of R₄ include those definedpreviously for compounds (IB)′.

In another embodiment, a stereochemical isomer enriched in the (1S,5R)configuration or (1R,5R) configuration of formula (IE)′ or a saltthereof is provided, wherein G is 2-pyridyl or 3-pyridyl and R₁, p, R₃and R₄ are as defined for formula (I):

In Formula (IE)′, in one embodiment, G corresponds to 2-pyridyl(Compounds (IE₁)′) and in another embodiment to 3-pyridyl (Compounds(IE₂)′), as illustrated below:

The configuration will then change depending on the type of pyridinering, as mentioned above.

In Formulae (IE)′, (IE₁)′ and (IE₂)′, in one embodiment, R₃ is methyl.R₄ may be phenyl, heterocyclyl, 5- or 6-membered heteroaromatic group ora 9- to 11-membered bicyclic group, any of which is optionallysubstituted by 1, 2, 3 or 4 substituents selected from the groupconsisting of: halogen, hydroxy, oxo, cyano, nitro, C₁₋₄alkyl,fluoroC₁₋₄alkyl, C₁₋₄alkoxy, fluoroC₁₋₄alkoxy, C₁₋₄alkanoyl; and when R₁is chlorine and p is 1, such R₁ is not present in the ortho positionwith respect to the linking bond to the rest of the molecule.

Examples of R₄ include those defined previously for compounds (IB)′.

In another embodiment, a stereochemical isomer enriched in the (1S,5R)configuration of formula (IF)′ or a salt thereof is provided, whereinR₁, p, R₃ and R₄ are as defined for formula (I):

In Formula (IF)′, in one embodiment, R₃ is methyl. R₄ may be phenyl,heterocyclyl, 5- or 6-membered heteroaromatic group or a 9- to11-membered bicyclic group, any of which is optionally substituted by 1,2, 3 or 4 substituents selected from the group consisting of: halogen,hydroxy, oxo, cyano, nitro, C₁₋₄alkyl, fluoroC₁₋₄alkyl, C₁₋₄alkoxy,fluoroC₁₋₄alkoxy, C₁₋₄alkanoyl; and when R₁ is chlorine and p is 1, suchR₁ is not present in the ortho position with respect to the linking bondto the rest of the molecule. Examples of R₄ include those definedpreviously for compounds (IB)′.

Certain of the compounds of the invention may form acid addition saltswith one or more equivalents of the acid. The present invention includeswithin its scope all possible stoichiometric and non-stoichiometricforms.

Pharmaceutical acceptable salts may also be prepared from other salts,including other pharmaceutically acceptable salts, of the compound offormula (I) using conventional methods.

Those skilled in the art of organic chemistry will appreciate that manyorganic compounds can form complexes with solvents in which they arereacted or from which they are precipitated or crystallized. Thesecomplexes are known as “solvates”. For example, a complex with water isknown as a “hydrate”. Solvates of the compound of the invention arewithin the scope of the invention. The compounds of formula (I) mayreadily be isolated in association with solvent molecules bycrystallisation or evaporation of an appropriate solvent to give thecorresponding solvates.

In addition, prodrugs are also included within the context of thisinvention. As used herein, the term “prodrug” means a compound which isconverted within the body, e.g. by hydrolysis in the blood, into itsactive form that has medical effects. Pharmaceutically acceptableprodrugs are described in T. Higuchi and V. Stella, Prodrugs as NovelDelivery Systems, Vol. 14 of the A.C.S. Symposium Series, Edward B.Roche, ed., Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press, 1987, and in D. Fleisher,S. Ramon and H. Barbra “Improved oral drug delivery: solubilitylimitations overcome by the use of prodrugs”, Advanced Drug DeliveryReviews (1996) 19(2) 115-130, each of which are incorporated herein byreference.

Prodrugs are any covalently bonded carriers that release a compound ofstructure (I) in vivo when such prodrug is administered to a patient.Prodrugs are generally prepared by modifying functional groups in a waysuch that the modification is cleaved, either by routine manipulation orin vivo, yielding the parent compound. Prodrugs include, for example,compounds of this invention wherein hydroxy, amine or sulfhydryl groupsare bonded to any group that, when administered to a patient, cleaves toform the hydroxy, amine or sulfhydryl groups. Thus, representativeexamples of prodrugs include (but are not limited to) acetate, formateand benzoate derivatives of alcohol, sulfhydryl and amine functionalgroups of the compounds of structure (I). Further, in the case of acarboxylic acid (—COOH), esters may be employed, such as methyl esters,ethyl esters, and the like. Esters may be active in their own rightand/or be hydrolysable under in vivo conditions in the human body.Suitable pharmaceutically acceptable in vivo hydrolysable ester groupsinclude those which break down readily in the human body to leave theparent acid or its salt.

Furthermore, some of the crystalline forms of the compounds of structure(I) may exist as polymorphs, which are included in the presentinvention.

Those skilled in the art will appreciate that in the preparation of thecompound of the invention or a solvate thereof it may be necessaryand/or desirable to protect one or more sensitive groups in the moleculeto prevent undesirable side reactions. Suitable protecting groups foruse according to the present invention are well known to those skilledin the art and may be used in a conventional manner. See, for example,“Protective groups in organic synthesis” by T. W. Greene and P. G. M.Wuts (John Wiley & sons 1991) or “Protecting Groups” by P. J. Kocienski(Georg Thieme Verlag 1994). Examples of suitable amino protecting groupsinclude acyl type protecting groups (e.g. formyl, trifluoroacetyl,acetyl), aromatic urethane type protecting groups (e.g.benzyloxycarbonyl (Cbz) and substituted Cbz), aliphatic urethaneprotecting groups (e.g. 9-fluorenylmethoxycarbonyl (Fmoc),t-butyloxycarbonyl (Boc), isopropyloxycarbonyl, cyclohexyloxycarbonyl)and alkyl type protecting groups (e.g. benzyl, trityl, chlorotrityl).Examples of suitable oxygen protecting groups may include for examplealky silyl groups, such as trimethylsilyl or tert-butyldimethylsilyl;alkyl ethers such as tetrahydropyranyl or tert-butyl; or esters such asacetate

When a specific enantiomer of a compound of general formula (I) isrequired, this may be obtained for example by resolution of acorresponding enantiomeric mixture of a compound of formula (I) usingconventional methods. Thus the required enantiomer may be obtained fromthe racemic compound of formula (I) by use of chiral HPLC procedure.

The subject invention also includes isotopically-labelled compounds,which are identical to those recited in formula (I) and following, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the invention and pharmaceutically acceptable saltsthereof include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, sulphur, fluorine, iodine, and chlorine, such as ²H, ³H,¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I and ¹²⁵I.

Compounds of the present invention and pharmaceutically acceptable saltsof said compounds that contain the aforementioned isotopes and/or otherisotopes of other atoms are within the scope of the present invention.Isotopically-labelled compounds of the present invention, for examplethose into which radioactive isotopes such as ³H, ¹⁴C are incorporated,are useful in drug and/or substrate tissue distribution assays.Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes are particularlypreferred for their ease of preparation and detectability. ¹¹C and ¹⁸Fisotopes are particularly useful in PET (positron emission tomography),and ¹²⁵I isotopes are particularly useful in SPECT (single photonemission computerized tomography), all useful in brain imaging. Further,substitution with heavier isotopes such as deuterium, i.e., ²H, canafford certain therapeutic advantages resulting from greater metabolicstability, for example increased in vivo half-life or reduced dosagerequirements and, hence, may be preferred in some circumstances.Isotopically labelled compounds of formula I and following of thisinvention can generally be prepared by carrying out the proceduresdisclosed in the Schemes and/or in the Examples below, by substituting areadily available isotopically labelled reagent for a non-isotopicallylabelled reagent.

Certain groups/substituents included in the present invention may bepresent as isomers. The present invention includes within its scope allsuch isomers, including racemates, enantiomers, tautomers and mixturesthereof. Certain of the substituted heteroaromatic groups included incompounds of formula (I) may exist in one or more tautomeric forms. Thepresent invention includes within its scope all such tautomeric forms,including mixtures.

In one embodiment of the present invention compounds are provided e amolecular weight of 800 or less. In another embodiment compounds areprovided having a molecular weight of 600 or less. Generally, andwithout being limited thereto, such compounds may have higher oralbioavailability, and sometimes higher solubility and/or brainpenetrancy. Molecular weight here refers to that of the unsolvated freebase compound, excluding any molecular weight contributed by additionsalts, solvent (e.g. water) molecules, prodrug molecular parts cleavedoff in vivo, etc.

In general, the compounds or salts of the invention should beinterpreted as excluding those compounds (if any) which are sochemically unstable, either per se or in water, that they are clearlyunsuitable for pharmaceutical use through all administration routes,whether oral, parenteral or otherwise. Such compounds are known to theskilled chemist. Prodrugs or compounds which are stable ex vivo andwhich are convertable in the mammalian (e.g. human) body to theinventive compounds are however included.

Example compounds of the present invention include:

-   5-[5-({3-[(1R,5S/1S,5R)-1-(4-Methoxyphenyl)-3-azabicyclo[3.1.0]hex-3-yl]propyl}-thio)-4-methyl-4H-1,2,4-triazol-3-yl]-2-methylquinoline;-   5-[5-({3-[(1S,5R)-1-(4-Methoxyphenyl)-3-azabicyclo[3.1.0]hex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazol-3-yl]-2-methylquinoline,    Enantiomer 1;-   5-[5-({3-[(1R,5S/1S,5R)-1-(4-Bromophenyl)-3-azabicyclo[3.1.0]hex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazol-3-yl]-2-methylquinoline;-   5-[5-({3-[(1S,5R)-1-(4-Bromophenyl)-3-azabicyclo[3.1.0]hex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazol-3-yl]-2-methylquinoline,    Enantiomer 2;-   2-Methyl-5-[4-methyl-5-({3-[(1R,5S/1S,5R)-1-phenyl-3-azabicyclo[3.1.0]hex-3-yl]propyl}thio)-4H-1,2,4-triazol-3-yl]quinoline;-   2-Methyl-5-[4-methyl-5-({3-[(1S,5R)-1-phenyl-3-azabicyclo[3.1.0]hex-3-yl]propyl}thio)-4H-1,2,4-triazol-3-yl]quinoline,    Enantiomer 2;-   5-[5-({3-[(1R,5S/1S,5R)-1-(3,4-Dichlorophenyl)-3-azabicyclo[3.1.0]hex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazol-3-yl]-2-methylquinoline;-   5-[5-({3-[(1S,5R)-1-(3,4-Dichlorophenyl)-3-azabicyclo[3.1.0]hex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazol-3-yl]-2-methylquinoline,    Enantiomer 1;-   5-[5-({3-[(1R,5S/1S,5R)-1-(4-tert-Butylphenyl)-3-azabicyclo[3.1.0]hex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazol-3-yl]-2-methylquinoline;-   5-[5-({3-[(1S,5R)-1-(4-tert-Butylphenyl)-3-azabicyclo[3.1.0]hex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazol-3-yl]-2-methylquinoline,    Enantiomer 2;-   4-[(1R,5S/1S,5R)-3-(3-{[4-Methyl-5-(2-methylquinolin-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]benzonitrile;-   4-[(1R,5S/1S,5R)-3-(3-{[4-Methyl-5-(2-methylquinolin-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]phenol;-   (1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-phenyl-3-azabicyclo[3.1.0]hexane;-   (1R,5S/1S,5R)-1-(4-Bromophenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-1-(4-Bromophenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane,    Enantiomer 1;-   (1R,5S/1S,5R)-1-(4-tert-Butylphenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1R,5S/1S,5R)-1-(3,4-Dichlorophenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-1-(3,4-Dichlorophenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane,    Enantiomer 2;-   (1R,5S/1S,5R)-1-(4-methoxyphenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-1-(4-methoxyphenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane,    Enantiomer 2;-   (1R,5S/1S,5R)-1-[4-(5-methyl-3-isoxazolyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-3-(3-{[4-Methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;    (1S,5R)-3-(3-{[4-Methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;-   (1R,5S/1S,5R)-1-[2-Fluoro-4-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1R,5S/1S,5R)-3-(3-{[4-Methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[3-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;-   (1R,5S/1S,5R)-1-[4-Fluoro-3-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   1-[5-[(1S,5R/1R,5S)-3-(3-{[4-Methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]-2-(methyloxy)phenyl]ethanone;-   1-[5-[(1S,5R)-3-(3-{[4-Methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]-2-(methyloxy)phenyl]ethanone,    Enantiomer 1;-   (1S,5R/1R,5S)-1-(4-Chlorophenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-1-(4-Chlorophenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane,    Enantiomer 1;-   (1S,5R/1R,5S)-1-(4-Fluorophenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-1-(4-Fluorophenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane,    Enantiomer 1;-   (1S,5R/1R,5S)-1-(3-Chlorophenyl)-5-methyl-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-1-(3-Chlorophenyl)-5-methyl-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane,    Enantiomer 1;-   (1S,5R/1R,5S)-1-(3-Fluorophenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-1-(3-Fluorophenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane,    Enantiomer 1;-   (1S,5R/1R,5S)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[3-(methyloxy)phenyl]-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[3-(methyloxy)phenyl]-3-azabicyclo[3.1.0]hexane,    Enantiomer 1;-   (1S,5R)-1-(4-Bromophenyl)-3-(3-{[4-methyl-5-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-1-(4-Bromophenyl)-3-[3-({4-methyl-5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}thio)propyl]-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-1-(4-Bromophenyl)-3-(3-{[4-methyl-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl]thio}-propyl)-3-azabicyclo[3.1.0]hexane,-   (1S,5R)-1-(4-Bromophenyl)-3-(3-{[5-(3,4-difluorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   5-[5-({3-[(1S,5R/1R,5S)-1-(4-Chlorophenyl)-3-azabicyclo[3.1.0]hex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazol-3-yl]-2-methylquinoline;-   5-[5-({3-[(1S,5R/1R,5S)-1-(4-Chlorophenyl)-3-azabicyclo[3.1.0]hex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazol-3-yl]-2-methylquinoline,    Enantiomer 1;-   (1S,5R/1R,5S)-3-(3-{[4-Methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-{4-[(trifluoromethyl)oxy]phenyl}-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-3-(3-{[4-Methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}-propyl)-1-{4-[(trifluoromethyl)oxy]phenyl}-3-azabicyclo[3.1.0]hexane,    Enantiomer 1-   (1S,5R/1R,5S)-3-(3-{[4-Methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]-thio}propyl)-1-[2-methyl-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;-   (1S,5R/1R,5S)-3-(3-{[4-Methyl-5-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-{4-[(trifluoromethyl)oxy]phenyl}-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-3-(3-{[4-Methyl-5-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-{4-[(trifluoromethyl)oxy]phenyl}-3-azabicyclo[3.1.0]hexane,    Enantiomer 2;-   (1R,5S/1S,5R)-1-(3-Bromophenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-3-(1-Methyl-3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-3-(1-Methyl-3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane,    Diastereoisomer 1;-   (1S,5R)-3-(1-Methyl-3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane,    Diastereoisomer 2;-   (1R,5S/1S,5R)-1-[2-Fluoro-5-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-1-[2-Fluoro-5-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane,    Enantiomer 2;-   1-[4-[(1R,5S/1S,5R)-3-(3-{[4-Methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]-2-(methyloxy)phenyl]ethanone;-   1-[4-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]-2-(methyloxy)phenyl]-1-propanone;-   (1R,5S/1S,5R)-3-(3-{[4-Methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[2-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-1-[2-Fluoro-4-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-3-(3-{[4-Methyl-5-(2-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-3-(3-{[4-Methyl-5-(4-pyridazinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-3-(3-{[5-(1,5-Dimethyl-1H-pyrazol-4-yl)-4-methyl-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-3-(3-{[4-Methyl-5-(5-pyrimidinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-3-(3-{[4-Methyl-5-(3-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-3-(3-{[4-Methyl-5-(6-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-3-(3-{[5-(2,4-Dimethyl-1,3-thiazol-5-yl)-4-methyl-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-3-(3-{[4-Methyl-5-(5-methyl-2-pyrazinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-3-(3-{[4-Methyl-5-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;-   2-Methyl-6-{4-methyl-5-[(3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)thio]-4H-1,2,4-triazol-3-yl}quinoline;-   8-Fluoro-2-methyl-5-{4-methyl-5-[(3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)thio]-4H-1,2,4-triazol-3-yl}quinoline;-   2-Methyl-5-{4-methyl-5-[(3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)thio]-4H-1,2,4-triazol-3-yl}quinoline;-   (1S,5R)-1-[2-Fluoro-4-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(2-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-1-[2-Fluoro-4-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-pyridazinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-1-[2-Fluoro-4-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(5-pyrimidinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-3-(3-{[5-(2,4-Dimethyl-1,3-thiazol-5-yl)-4-methyl-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;    (1S,5R)-1-[2-Fluoro-4-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(5-methyl-2-pyrazinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-1-[2-Fluoro-4-(trifluoromethyl)phenyl]-3-[3-({4-methyl-5-[4-(trifluoro-methyl)phenyl]-4H-1,2,4-triazol-3-yl}thio)propyl]-3-azabicyclo[3.1.0]hexane;-   1-{4-[(1R,5S/1S,5R)-3-(3-{[4-Methyl-5-(2-methyl-5-quinolinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]phenyl}-2-pyrrolidinone;-   5-{5-[(3-{(1R,5S/1S,5R)-1-[4-(1,1-Dioxido-2-isothiazolidinyl)phenyl]-3-azabicycle-[3.1.0]hex-3-yl}propyl)thio]-4-methyl-4H-1,2,4-triazol-3-yl}-2-methylquinoline;-   (1R,5S/1S,5R)-1-[3-Fluoro-4-(trifluoromethyl)phenyl]-5-methyl-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   1-(2-(Methyloxy)-5-{(1R,5S/1S,5R)-3-[3-({4-methyl-5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}thio)propyl]-3-azabicyclo[3.1.0]hex-1-yl}phenyl)ethanone;-   1-[5-[(1R,5S/1S,5R)-3-(3-{[5-(3,4-Difluorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]-2-(methyloxy)phenyl]ethanone;-   1-{2-(Methyloxy)-5-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]phenyl}ethanone;-   1-[5-[(1R,5S/1S,5R)-3-(3-{[4-Methyl-5-(2-methyl-5-quinolinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]-2-(methyloxy)phenyl]ethanone;-   1-{2-(Methyloxy)-5-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]phenyl}ethanone;-   1-(2-Hydroxy-5-{(1R,5S/1S,5R)-3-[3-({4-methyl-5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}thio)propyl]-3-azabicyclo[3.1.0]hex-1-yl}phenyl)ethanone;-   1-{5-[(1R,5S/1S,5R)-3-(3-{[5-(3,4-Difluorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]-2-hydroxyphenyl}ethanone;-   1-{2-Hydroxy-5-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]phenyl}ethanone;-   1-{2-Hydroxy-5-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(2-methyl-5-quinolinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]phenyl}ethanone;-   1-[5-[(1R,5S/1S,5R)-3-(3-{[4-Methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]-2-(methyloxy)phenyl]-1-propanone;-   1-[5-[(1S,5R)-3-(3-{[4-Methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}-propyl)-3-azabicyclo[3.1.0]hex-1-yl]-2-(methyloxy)phenyl]-1-propanone    Enantiomer 1;-   2-Methyl-5-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]-1,3-benzothiazole;-   2-Methyl-5-[(1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]-1,3-benzothiazole,    Enantiomer 1;-   2-Methyl-6-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]-1,3-benzothiazole;-   1-Methyl-5-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]-1H-indazole;-   1-Methyl-5-[(1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]-1H-indazole,    Enantiomer 1;-   (1R,5S/1S,5R)-3-(3-{[4-Methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane;-   (1R,5S/1S,5R)-1-(4-Bromophenyl)-3-(3-{[4-methyl-5-(2-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1R,5S/1S,5R)-1-(4-Bromophenyl)-3-(3-{[4-methyl-5-(4-pyridazinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1R,5S/1S,5R)-1-(4-Bromophenyl)-3-(3-{[5-(5-chloro-1-methyl-1H-pyrazol-4-yl)-4-methyl-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1R,5S/1S,5R)-1-(4-Bromophenyl)-3-(3-{[4-methyl-5-(1-methyl-1H-1,2,3-triazol-4-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1R,5S/1S,5R)-1-(4-Bromophenyl)-3-(3-{[5-(1,5-dimethyl-1H-pyrazol-4-yl)-4-methyl-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1R,5S/1S,5R)-1-(4-Bromophenyl)-3-(3-{[4-methyl-5-(5-pyrimidinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1R,5S/1S,5R)-1-(4-Bromophenyl)-3-[3-({4-methyl-5-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-4H-1,2,4-triazol-3-yl}thio)propyl]-3-azabicyclo[3.1.0]hexane;-   (1R,5S/1S,5R)-1-(4-Bromophenyl)-3-(3-{[4-methyl-5-(3-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1R,5S/1S,5R)-1-(4-Bromophenyl)-3-(3-{[4-methyl-5-(3-methyl-5-isoxazolyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1R,5S/1S,5R)-1-(4-Bromophenyl)-3-(3-{[4-methyl-5-(6-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1R,5S/1S,5R)-1-(4-Bromophenyl)-3-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1R,5S/1S,5R)-1-(4-Bromophenyl)-3-(3-{[4-methyl-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1R,5S/1S,5R)-1-(4-Bromophenyl)-3-[3-({4-methyl-5-[2-methyl-5-(trifluoromethyl)-1,3-oxazol-4-yl]-4H-1,2,4-triazol-3-yl}thio)propyl]-3-azabicyclo[3.1.0]hexane;-   (1R,5S/1S,5R)-1-(4-Bromophenyl)-3-(3-{[4-methyl-5-(3-methyl-2-pyridinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1R,5S/1S,5R)-1-(4-Bromophenyl)-3-(3-{[5-(2,4-dimethyl-1,3-thiazol-5-yl)-4-methyl-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1R,5S/1S,5R)-1-(4-Bromophenyl)-3-(3-{[5-(2,5-dimethyl-3-furanyl)-4-methyl-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1R,5S/1S,5R)-1-(4-Bromophenyl)-3-(3-{-[5-(5-chloro-2-thienyl)-4-methyl-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1R,5S/1S,5R)-1-(4-Bromophenyl)-3-(3-{[4-ethyl-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1R,5S/1S,5R)-1-(4-Bromophenyl)-3-[3-({4-methyl-5-[2-methyl-6-(trifluoromethyl)-3-pyridinyl]-4H-1,2,4-triazol-3-yl}thio)propyl]-3-azabicyclo[3.1.0]hexane.-   5-[5-({3-[(1R,5S/1S,5R)-1-(4-Bromophenyl)-3-azabicyclo[3.1.0]hex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazol-3-yl]-1-methyl-3-(trifluoromethyl)-1H-thieno[2,3-c]pyrazole;-   3-(3-{[4-Methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-(1R,5R/1S,5S)-1-[5-(trifluoromethyl)-2-pyridinyl]-3-azabicyclo[3.1.0]hexane;-   3-(3-{[4-Methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-(1R,5R)-1-[5-(trifluoromethyl)-2-pyridinyl]-3-azabicyclo[3.1.0]hexane,    Enantiomer 2;-   3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-(1R,5R/1S,5S)-1-[6-(trifluoromethyl)-2-pyridinyl]-3-azabicyclo[3.1.0]hexane;-   (1R,5S/1S,5R)-1-[3-Fluoro-4-(1H-pyrrol-1-ylmethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1S,5R/1R,5S)-3-(3-{[4-Methyl-5-(5-methyl-2-pyrazinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane;-   (1S,5R/1R,5S)-3-(3-{[4-Methyl-5-(6-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane;-   (1S,5R/1R,5S)-3-(3-{[4-Methyl-5-(2-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane;-   (1S,5R/1R,5S)-3-{3-[(4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl)thio]propyl}-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane;-   (1S,5R/1R,5S)-3-(3-{[5-(2,4-Dimethyl-1,3-thiazol-5-yl)-4-methyl-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane;-   (1S,5R/1R,5S)-3-[3-({4-Methyl-5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}thio)propyl]-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane;-   (1S,5R/1R,5S)-2-Methyl-5-[3-(3-{[4-methyl-5-(5-methyl-2-pyrazinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]-1,3-benzothiazole;-   (1S,5R/1R,5S)-2-Methyl-5-[3-(3-{[4-methyl-5-(6-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]-1,3-benzothiazole;-   (1S,5R/1R,5S)-2-Methyl-5-(3-{3-[(4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)thio]propyl}-3-azabicyclo[3.1.0]hex-1-yl)-1,3-benzothiazole;-   (1S,5R/1R,5S)-5-[3-(3-{[5-(2,4-Dimethyl-1,3-thiazol-5-yl)-4-methyl-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]-2-methyl-1,3-benzothiazole;-   (1S,5R/1R,5S)-2-Methyl-5-{3-[3-({4-methyl-5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}thio)propyl]-3-azabicyclo[3.1.0]hex-1-yl}-1,3-benzothiazole;-   (1R,5S/1S,5R)-1-[3-Fluoro-5-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-azabicyclo[3.1.0]hexane;-   (1S,5R)-1-[3-Fluoro-5-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-azabicyclo[3.1.0]hexane,    Enantiomer 1;-   (1R,5S/1S,5R)-1-[2-Fluoro-3-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-azabicyclo[3.1.0]hexane;-   (1S,5R)-1-[2-Fluoro-3-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-azabicyclo[3.1.0]hexane,    Enantiomer 2;-   (1R,5S/1S,5R)-1-[4-(Methyloxy)-5-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-azabicyclo[3.1.0]hexane;-   (1R,5S/1S,5R)-1-[4-(4-Chloro-2-fluorophenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-azabicyclo[3.1.0]hexane;-   (1R,5S/1S,5R)-1-[3-(2-{[4-Methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-{3-[(trifluoromethyl)oxy]phenyl}-3-azabicyclo[3.1.0]hexane;-   (1R,5S/1S,5R)-1-(2-Chloro-4-methylphenyl)-3-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1R,5S/1S,5R)-1-[3-Chloro-4-(methyloxy)phenyl]-3-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1R,5S/1S,5R)-1-[4-(2,4-Dimethyl-1,3-thiazol-5-yl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-{4-[6-(trifluoromethyl)-2-pyridinyl]phenyl}-3-azabicyclo[3.1.0]hexane;-   (1R,5S/1S,5R)-1-[3-(2,4-dimethyl-1,3-thiazol-5-yl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[3-(5-methyl-2-thienyl)phenyl]-3-azabicyclo[3.1.0]hexane;-   (1R,5S/1S,5R)-1-[4-(3,5-dimethyl-4-isoxazolyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-3-(3-{[5-(2,4-Dimethyl-1,3-oxazol-5-yl)-4-methyl-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane    and pharmaceutically acceptable salts thereof.

Example compounds of the present invention include the following, whichare obtainable by the processes of the present invention:

-   4-[(1S,5R)-3-(3-{[4-Methyl-5-(2-methylquinolin-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]benzonitrile;-   4-[(1S,5R)-3-(3-{[4-Methyl-5-(2-methylquinolin-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]phenol;-   (1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-phenyl-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-1-(4-tert-Butylphenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-1-[4-(5-methyl-3-isoxazolyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-3-(3-{[4-Methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[3-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-1-[4-Fluoro-3-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-3-(3-{[4-Methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]-thio}propyl)-1-[2-methyl-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-1-(3-Bromophenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   1-[4-[(1S,5R)-3-(3-{[4-Methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]-2-(methyloxy)phenyl]ethanone;-   1-[4-[(1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]-2-(methyloxy)phenyl]-1-propanone;-   (1S,5R)-3-(3-{[4-Methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[2-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;-   1-{4-[(1S,5R)-3-(3-{[4-Methyl-5-(2-methyl-5-quinolinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]phenyl}-2-pyrrolidinone;-   5-{5-[(3-{(1S,5R)-1-[4-(1,1-Dioxido-2-isothiazolidinyl)phenyl]-3-azabicycle[3.1.0]hex-3-yl}propyl)thio]-4-methyl-4H-1,2,4-triazol-3-yl}-2-methylquinoline;-   1-(2-(Methyloxy)-5-{(1S,5R)-3-[3-({4-methyl-5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}thio)propyl]-3-azabicyclo[3.1.0]hex-1-yl}phenyl)ethanone;-   1-[5-[(1S,5R)-3-(3-{[5-(3,4-Difluorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]-2-(methyloxy)phenyl]ethanone;-   1-{2-(Methyloxy)-5-[(1S,5R)-3-(3-{[4-methyl-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]phenyl}ethanone;-   1-[5-[(1S,5R)-3-(3-{[4-Methyl-5-(2-methyl-5-quinolinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]-2-(methyloxy)phenyl]ethanone;-   1-{2-(Methyloxy)-5-[(1S,5R)-3-(3-{[4-methyl-5-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]phenyl}ethanone;-   1-(2-Hydroxy-5-{(1S,5R)-3-[3-({4-methyl-5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}thio)propyl]-3-azabicyclo[3.1.0]hex-1-yl}phenyl)ethanone;-   1-{5-[(1S,5R)-3-(3-{[5-(3,4-Difluorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]-2-hydroxyphenyl}ethanone;-   1-{2-Hydroxy-5-[(1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]phenyl}ethanone;-   1-{2-Hydroxy-5-[(1S,5R)-3-(3-{[4-methyl-5-(2-methyl-5-quinolinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]phenyl}ethanone;-   2-Methyl-6-[(1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]-1,3-benzothiazole;-   (1S,5R)-3-(3-{[4-Methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-1-(4-Bromophenyl)-3-(3-{[4-methyl-5-(2-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-1-(4-Bromophenyl)-3-(3-{[4-methyl-5-(4-pyridazinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-1-(4-Bromophenyl)-3-(3-{[5-(5-chloro-1-methyl-1H-pyrazol-4-yl)-4-methyl-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-1-(4-Bromophenyl)-3-(3-{[4-methyl-5-(1-methyl-1H-1,2,3-triazol-4-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-1-(4-Bromophenyl)-3-(3-{[5-(1,5-dimethyl-1H-pyrazol-4-yl)-4-methyl-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-1-(4-Bromophenyl)-3-(3-{[4-methyl-5-(5-pyrimidinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-1-(4-Bromophenyl)-3-[3-({4-methyl-5-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-4H-1,2,4-triazol-3-yl}thio)propyl]-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-1-(4-Bromophenyl)-3-(3-{[4-methyl-5-(3-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-1-(4-Bromophenyl)-3-(3-{[4-methyl-5-(3-methyl-5-isoxazolyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-1-(4-Bromophenyl)-3-(3-{[4-methyl-5-(6-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-1-(4-Bromophenyl)-3-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-1-(4-Bromophenyl)-3-(3-{[4-methyl-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-1-(4-Bromophenyl)-3-[3-({4-methyl-5-[2-methyl-5-(trifluoromethyl)-1,3-oxazol-4-yl]-4H-1,2,4-triazol-3-yl}thio)propyl]-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-1-(4-Bromophenyl)-3-(3-{[4-methyl-5-(3-methyl-2-pyridinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-1-(4-Bromophenyl)-3-(3-{[5-(2,4-dimethyl-1,3-thiazol-5-yl)-4-methyl-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-1-(4-Bromophenyl)-3-(3-{[5-(2,5-dimethyl-3-furanyl)-4-methyl-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-1-(4-Bromophenyl)-3-(3-{-[5-(5-chloro-2-thienyl)-4-methyl-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-1-(4-Bromophenyl)-3-(3-{[4-ethyl-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-1-(4-Bromophenyl)-3-[3-({4-methyl-5-[2-methyl-6-(trifluoromethyl)-3-pyridinyl]-4H-1,2,4-triazol-3-yl}thio)propyl]-3-azabicyclo[3.1.0]hexane.-   5-[5-({3-[(1S,5R)-1-(4-Bromophenyl)-3-azabicyclo[3.1.0]hex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazol-3-yl]-1-methyl-3-(trifluoromethyl)-1H-thieno[2,3-c]pyrazole;-   3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-(1R,5R)-1-[6-(trifluoromethyl)-2-pyridinyl]-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-1-[3-Fluoro-4-(1H-pyrrol-1-ylmethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-3-(3-{[4-Methyl-5-(5-methyl-2-pyrazinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-3-(3-{[4-Methyl-5-(6-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-3-(3-{[4-Methyl-5-(2-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-3-{3-[(4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl)thio]propyl}-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-3-(3-{[5-(2,4-Dimethyl-1,3-thiazol-5-yl)-4-methyl-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-3-[3-({4-Methyl-5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}thio)propyl]-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-2-Methyl-5-[3-(3-{[4-methyl-5-(5-methyl-2-pyrazinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]-1,3-benzothiazole;-   (1S,5R)-2-Methyl-5-[3-(3-{[4-methyl-5-(6-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]-1,3-benzothiazole;-   (1S,5R)-2-Methyl-5-(3-{3-[(4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)thio]propyl}-3-azabicyclo[3.1.0]hex-1-yl)-1,3-benzothiazole;-   (1S,5R)-5-[3-(3-{[5-(2,4-Dimethyl-1,3-thiazol-5-yl)-4-methyl-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]-2-methyl-1,3-benzothiazole;-   (1S,5R/1R,5S)-2-Methyl-5-{3-[3-({4-methyl-5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}thio)propyl]-3-azabicyclo[3.1.0]hex-1-yl}-1,3-benzothiazole;-   (1S,5R)-1-[4-(4-Chloro-2-fluorophenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-azabicyclo[3.1.0]hexane;-   (1S,5R)-1-[3-(2-{[4-Methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-{3-[(trifluoromethyl)oxy]phenyl}-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-1-(2-Chloro-4-methylphenyl)-3-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-1-[3-Chloro-4-(methyloxy)phenyl]-3-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-1-[4-(2,4-Dimethyl-1,3-thiazol-5-yl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-{4-[6-(trifluoromethyl)-2-pyridinyl]phenyl}-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-1-[3-(2,4-dimethyl-1,3-thiazol-5-yl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[3-(5-methyl-2-thienyl)phenyl]-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-1-[4-(3,5-dimethyl-4-isoxazolyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;-   (1S,5R)-3-(3-{[5-(2,4-Dimethyl-1,3-oxazol-5-yl)-4-methyl-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane    and pharmaceutically acceptable salts thereof.

The present invention also provides a process for preparing a compoundof formula (I) or a salt thereof as defined above.

The process of the present invention for preparing compounds of formula(I) in which G is a phenyl derivative, comprises the steps of:

(a) reacting a compound of formula (II):

wherein R₁ and p are as defined for formula (I), with a compound offormula (III):

wherein R₂, R₃ and R₄ are as defined for formula (I) and X is a leavinggroup,or(b) for a compound of formula (I) wherein p is 1 or 2, reacting acompound of formula (IV):

wherein R₁, R₂, R₃, and R₄ are as defined for formula (I), p is 0 or 1and Y is halogen, a perfluoroalkylsulfonyloxy group (e.g.trifluoromethylsulfonyloxy), or Y is a group M selected from a boronderivative (e.g. a boronic acid function B(OH)₂) or a metal functionsuch as trialkylstannyl (e.g. SnBu₃), zinc halide or magnesium halide;with a compound R1-Y1, wherein Y1 is halogen when Y is a group M; orwhen Y is halogen or a perfluoroalkylsulfonyloxy group Y1 is a group Mas defined above or hydrogen that can be activated by a suitable base(e.g. Cs₂CO₃) in the presence of a suitable transition metal (e.g. Pd);“leaving group” is as understood by a skilled chemist, i.e. a groupwhich can be displaced by a nucleophile in e.g. a S_(N)2, S_(N)1 orS_(N)Ar type reaction;and thereafter optionally for process (a) or process (b):(i) removing any protecting group(s); and/or(ii) forming a salt; and/or(iii) converting a compound of formula (I) or a salt thereof to anothercompound of formula (I) or a salt thereof.

Process (a) may be performed using conventional methods for theformation of a tertiary amine. The leaving group X can be halogen suchas chlorine. Alternatively X can be a sulfonyloxy group suchC₁₋₄alkylsulfonyloxy (e.g. methanesulfonyloxy), C₁₋₄alkylsulfonyloxy orhaloC₁₋₄alkylsulfonyloxy (e.g. trifluoromethanesulfonyloxy); orarylsulfonyloxy wherein aryl is optionally substituted phenyl, anoptionally substituted 5- or 6-membered heteroaromatic group, or anoptionally substituted bicyclic group, for example optionallysubstituted phenyl, wherein in each case the optional substituents areone or more C₁₋₂alkyl groups; e.g. para-toluenesulfonyloxy. When X is ahalogen the reaction may be carried out using a base such as potassiumcarbonate in the presence of a source of iodide such as sodium iodide ina solvent such as N,N-dimethylformamide at a suitable temperature, e.g.60° C.

Compounds of formula (II) may be prepared by methods well known in theart (e.g. J. Med. Chem. 1981, 24, 481-490). For typical conditions seePreparations 1-6 and 15-18 hereinafter. Interconversion of groups R₁ maybe affected by methodology well known in the art (e.g. demethylation ofa methoxy group resulting in a hydroxy group using a suitable Lewisacidic reagent such as boron tribromide in an inert solvent such asdichloromethane). Preparations 7-11 hereinafter give additional examplesof such interconversions in the presence of a suitable protecting groupfor the secondary amine, such as N-trifluoroacetyl.

Reaction of a compound of formula (IV) with R1-Y1 according to process(b) may be effected in the presence of a transition metal e.g.,palladium catalyst such as bis-triphenylphosphinepalladium dichloride,tetrakis-triphenylphosphinepalladium (0) or the complex formed in situfrom tris(dibenzylideneacetone) dipalladium(0) and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene. When M is a boronicacid function such as B(OH)₂ the reaction may be carried out under basicconditions, for example using aqueous sodium carbonate in a suitablesolvent such as dioxane. When M is trialkylstannyl the reaction may becarried out in an inert solvent, such as xylene or dioxane optionally inthe presence of LiCl. When M is a zinc or magnesium halide the reactionmay be effected in an aprotic solvent such as tetrahydrofuran. When M ishydrogen that can be activated by a suitable base (e.g. Cs₂CO₃) in thepresence of a suitable transition metal (e.g. Pd) the reaction may becarried out in an inert solvent such as dioxane in the presence of asuitable base such as Cs₂CO₃. The substituent Y may be halogen such asbromine, or a sulfonyloxy group such as trifluoromethylsulfonyloxy; andY1 is may be a group M, such as hydrogen that can be activated by asuitable base (e.g. Cs₂CO₃) in the presence of a suitable transitionmetal (e.g. Pd).

In one aspect of the present invention there is provided a syntheticprocess for the preparation of compounds of formula (II). The processmay be conveniently performed also for preparing compounds of formula(IIa), in which the phenyl moiety is replaced by pyridine, useful forpreparing compounds of formula (IE). This process comprises thefollowing steps:

wherein:

-   -   step (a′) means diazotation of an aniline (VII) followed by        reaction with maleimide to give 3-arylmaleimide (VIII);    -   step (b′) means cycloropanation of (VIII) to provide bicyclic        imide (IX);    -   step (c′) means reduction of imide (IX) to give compounds of        formula (II).

Step (a′) may be effected using conventional methods for the Meerweinreaction (e.g. J. Am. Chem. Soc. 1955, 77, 2313 describes the formationof arylmaleimides using this approach). Alternatively, in many casesthis step is suitably performed applying a procedure where to a mixtureof maleimide, an appropriate copper (II) salt such as anhydrous CuCl₂,and a suitable organonitrite, such as tert-butyl nitrite, in acompatible solvent, such as acetonitrile, is slowly added a solution ofa compound of formula (VII). This is followed by allowing time to reactas appropriate and a suitabe workup. Preparation 37 exemplifies thisprocess.

Step (b′) consists of slow addition of a solution of purified compoundof formula (VIII), or mixtures containing a compound of formula (VIII),dissolved in a suitable solvent such as dimethylsulfoxide, to a solutionof trimethylsulfoxonium iodide in a suitable solvent such asdimethylsulfoxide and a suitable base, such as sodium hydride. This isfollowed by allowing time to react as appropriate and a suitabe workup.Preparation 37 exemplifies this process.

Step (c′) can be performed using a suitable reducing agent in acompatible solvent, such as borane in tetrahydrofuran or Red-Al® intoluene at an appropriate temperature, such as for example 65° C. in thecase of borane as the reducing agent. This is followed by a suitabeworkup. Preparation 38 exemplifies this process.

In another aspect of the present invention an alternative syntheticprocess for the preparation of compounds of formula (II), or generallyof formula (XIII), is provided. This process comprises the followingsteps:

wherein:

R₁, p and G are as defined for formula (I), R₁₄O is a suitable alkoxygroup, PG is an appropriate protecting group and Y may be halogen suchas bromine, or a sulfonyloxy group such as trifluoromethylsulfonyloxyand comprising the following steps:

-   -   step (a″) means coupling reaction of a        (2,5-dihydro-1H-pyrrol-3-yl)boronate (X) with the aromatic        halogen or sulfonyloxy derivative (XI);    -   step (b″) means cycloropanation of (XII) followed by, if        appropriate, deprotection to provide bicyclic amine (XIII).

Step (a″) may be effected using conventional methods for the Suzukicoupling, e.g. using tetrakis(triphenylphosphine)palladium(0) as thesource of catalytic palladium(0) in the presence of cesium fluoride inan appropriate solvent such as tetrahydrofuran at a suitabletemperature. (R₁₄O)₂B may suitably be4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl and PG benzyl, representinga compound of structure (X) as reported in Synlett 2002, 5, 829-831.Preparation 50 exemplifies this process.

Step (b″) consists of a cyclopropanation reaction effected for exampleusing the reagent generated from trimethylsulfoxonium iodide and asuitable base such as sodium hydride, in a compatible solvent, forexample dimethylsulfoxide. Preparation 52 exemplifies this process. Thisis followed by a deprotection reaction as exemplified in Preparation 54.

A compound of formula (III) may itself be prepared by reacting acompound of formula (V):

wherein R₃ and R₄ are as hereinbefore defined; with a compound offormula (VI):

wherein X is defined as for formula (I) and L is a leaving group, e.g.,a bromine atom. For typical reaction conditions, see Preparation 13hereinafter.

Compounds of formula (I) where R₁, R₂, R₃, R₄, G and p are as abovedefined may be prepared by reacting a compound of formula (XIV):

wherein R₁, R₂, G and p are as defined for formula (I) and X is aleaving group, with a compound of formula (V):

wherein R₃ and R₄ are as hereinbefore defined. For typical reactionconditions when X is chlorine see Example 35 or alternatively Examples41-52.

A compound of formula (XIV) wherein R₁, G and p are as defined forformula (I), X is a leaving group and R₂ is H (hydrogen) can be preparedby alkylation of a compound of formula (XIII) in the presence of asuitable base such as a tertiary amine, for examplediisopropylethylamine, with a propyl derivative carrying two leavinggroups of preferrably differential reactivity in positions 1 and 3, forexample 1-bromo-3-chloropropane. Typical reaction conditions for thistransformation are given in Preparation 40.

A compound of formula (XIV) wherein R₁, G and p are as defined forformula (I), X is a leaving group and R₂ is C₁₋₄alkyl can be prepared bythe reaction between a beta-hydroxy ketone, for example4-hydroxy-2-butanone if R₂ is methyl, with a compound of formula (XIII)in the presence of a suitable borohydride source such as NaBH(OAc)₃,followed by conversion of the hydroxyl group into a leaving group bymethods known to the person skilled in the art, for example by theaction of thionyl chloride. Typical reaction conditions for thesetransformations are given in Preparations 19 and 20.

Interconversion reactions between compounds of formula (I) and saltsthereof may be performed using methods well known in the art. Examplesinclude:

(i) converting one or more of R₁ from alkoxy (e.g. methoxy) to hydroxy,(ii) converting one or more of R₁ from hydroxy to sulfonyloxy, such asalkylsulfonyloxy or haloalkylsulfonyloxy, e.g. methanesulfonyloxy oralkylsulfonyloxy or trifluoro-methanesulfonyloxy,(iii) converting one or more of R₁ from halogen orperfluoroalkylsulfonyloxy to cyano; and optionally thereafter forming asalt of formula (I).

Compounds of formula (I) have been found to exhibit affinity fordopamine receptors, in particular the D₃ receptor, and are expected tobe useful in the treatment of disease states which require modulation ofsuch receptors, such as psychotic conditions.

Such affinity is typically calculated from the IC₅₀ as the concentrationof a compound necessary to displace 50% of the radiolabeled ligand fromthe receptor, and is reported as a “K_(i)” value calculated by thefollowing equation:

$K_{i} = \frac{{IC}_{50}}{1 + {L/K_{D}}}$

where L=radioligand and K_(D)=affinity of radioligand for receptor(Cheng and Prusoff, Biochem. Pharmacol. 22:3099, 1973).

In the context of the present invention pKi (corresponding to theantilogarithm of Ki) is used instead of Ki and the compounds of thepresent invention typically show pKi greater than 7. In one aspect thepresent invention provides compounds of formula (I) having a pKicomprised between 7 and 8. In another aspect the present inventionprovides compounds of formula (I) having a pKi comprised between 8 and9. In a further aspect the present invention provides compounds offormula (I) having a pKi greater than 9.

Many of the compounds of formula (I) have also been found to havegreater affinity for dopamine D₃ than for D₂ receptors. The therapeuticeffect of currently available antipsychotic agents (neuroleptics) isgenerally believed to be exerted via blockade of D₂ receptors; howeverthis mechanism is also thought to be responsible for undesirableextrapyramidal side effects (eps) associated with many neurolepticagents. It has been suggested that blockade of the recentlycharacterised dopamine D₃ receptor may give rise to beneficialantipsychotic activity without significant eps. (see for exampleSokoloff et al, Nature, 1990; 347: 146-151; and Schwartz et al, ClinicalNeuropharmacology, Vol 16, No. 4, 295-314, 1993). In one embodimentcompounds of the present invention are provided which have higher (e.g.≧10× or ≧100× higher) affinity for dopamine D₃ than dopamine D₂receptors (such affinity can be measured using standard methodology forexample using cloned dopamine receptors—see herein). Said compounds maysuitably be used as selective modulators of D₃ receptors.

From the localisation of D₃ receptors, it could also be envisaged thatthe compounds could also have utility for the treatment of substanceabuse where it has been suggested that D₃ receptors are involved (e.g.see Levant, 1997, Pharmacol. Rev., 49, 231-252). Examples of suchsubstance abuse include alcohol, cocaine, heroin and nicotine abuse.Other conditions which may be treated by the compounds includedyskinetic disorders such as Parkinson's disease, neuroleptic-inducedparkinsonism and tardive dyskinesias; depression; anxiety, cognitiveimpairment including memory disorders such as Alzheimers disease, eatingdisorders, sexual dysfunction, sleep disorders, emesis, movementdisorders, obsessive-compulsive disorders, amnesia, aggression, autism,vertigo, dementia, circadian rhythm disorders and gastric motilitydisorders e.g. IBS.

Compounds of formula (I) may be used for treatment of all aspects ofdrug dependency including withdrawal symptoms from drugs of abuse suchas alcohol, cocaine, opiates, nicotine, benzodiazepines and inhibitionof tolerance induced by opioids. In addition, compounds of formula (I)and pharmaceutically acceptable salts and solvates thereof may be usedto reduce craving and therefore will be useful in the treatment of drugcraving. Drug craving can be defined as the incentive motivation toself-administer a psychoactive substance that was previously consumed.Three main factors are involved in the development and maintenance ofdrug craving: (1) Dysphoric states during drug withdrawal can functionas a negative reinforcer leading to craving; (2) Environmental stimuliassociated with drug effects can become progressively more powerful(sensitization) in controlling drug seeking or craving, and (3) Acognition (memory) of the ability of drugs to promote pleasurableeffects and to alleviate a dysphoric state during withdrawal. Cravingmay account for the difficulty that individuals have in giving up drugsof abuse and therefore contributes significantly to the development andmaintenance of drug dependence.

The compounds of formula (I) are of potential use as antipsychoticagents for example in the treatment of schizophrenia, schizo-affectivedisorders, psychotic depression, mania, paranoid and delusionaldisorders. Furthermore, they could have utility as adjunct therapy inParkinsons Disease, particularly with compounds such as L-DOPA andpossibly dopaminergic agonists, to reduce the side effects experiencedwith these treatments on long term use (e.g. see Schwartz et al., BrainRes. Reviews, 1998, 26, 236-242).

Within the context of the present invention, the terms describing theindications used herein are classified in the Diagnostic and StatisticalManual of Mental Disorders, 4th Edition, published by the AmericanPsychiatric Association (DSM-IV) and/or the International Classificationof Diseases, 10th Edition (ICD-10). The various subtypes of thedisorders mentioned herein are contemplated as part of the presentinvention. Numbers in brackets after the listed diseases below refer tothe classification code in DSM-IV.

Within the context of the present invention, the term “psychoticdisorder” includes:—

Schizophrenia including the subtypes Paranoid Type (295.30),Disorganised Type (295.10), Catatonic Type (295.20), UndifferentiatedType (295.90) and Residual Type (295.60); Schizophreniform Disorder(295.40); Schizoaffective Disorder (295.70) including the subtypesBipolar Type and Depressive Type; Delusional Disorder (297.1) includingthe subtypes Erotomanic Type, Grandiose Type, Jealous Type, PersecutoryType, Somatic Type, Mixed Type and Unspecified Type; Brief PsychoticDisorder (298.8); Shared Psychotic Disorder (297.3); Psychotic DisorderDue to a General Medical Condition including the subtypes With Delusionsand With Hallucinations; Substance-Induced Psychotic Disorder includingthe subtypes With Delusions (293.81) and With Hallucinations (293.82);and Psychotic Disorder Not Otherwise Specified (298.9).

Within the context of the present invention, the term “substance-relateddisorder” includes:—

Substance-related disorders including Substance Use Disorders such asSubstance Dependence, Substance Craving and Substance Abuse;Substance-Induced Disorders such as Substance Intoxication, SubstanceWithdrawal, Substance-Induced Delirium, Substance-Induced PersistingDementia, Substance-Induced Persisting Amnestic Disorder,Substance-Induced Psychotic Disorder, Substance-Induced Mood Disorder,Substance-Induced Anxiety Disorder, Substance-Induced SexualDysfunction, Substance-Induced Sleep Disorder and HallucinogenPersisting Perception Disorder (Flashbacks); Alcohol-Related Disorderssuch as Alcohol Dependence (303.90), Alcohol Abuse (305.00), AlcoholIntoxication (303.00), Alcohol Withdrawal (291.81), Alcohol IntoxicationDelirium, Alcohol Withdrawal Delirium, Alcohol-Induced PersistingDementia, Alcohol-Induced Persisting Amnestic Disorder, Alcohol-InducedPsychotic Disorder, Alcohol-Induced Mood Disorder, Alcohol-InducedAnxiety Disorder, Alcohol-Induced Sexual Dysfunction, Alcohol-InducedSleep Disorder and Alcohol-Related Disorder Not Otherwise Specified(291.9); Amphetamine (or Amphetamine-Like)-Related Disorders such asAmphetamine Dependence (304.40), Amphetamine Abuse (305.70), AmphetamineIntoxication (292.89), Amphetamine Withdrawal (292.0), AmphetamineIntoxication Delirium, Amphetamine Induced Psychotic Disorder,Amphetamine-Induced Mood Disorder, Amphetamine-Induced Anxiety Disorder,Amphetamine-Induced Sexual Dysfunction, Amphetamine-Induced SleepDisorder and Amphetamine-Related Disorder Not Otherwise Specified(292.9); Caffeine Related Disorders such as Caffeine Intoxication(305.90), Caffeine-Induced Anxiety Disorder, Caffeine-Induced SleepDisorder and Caffeine-Related Disorder Not Otherwise Specified (292.9);Cannabis-Related Disorders such as Cannabis Dependence (304.30),Cannabis Abuse (305.20), Cannabis Intoxication (292.89), CannabisIntoxication Delirium, Cannabis-Induced Psychotic Disorder,Cannabis-Induced Anxiety Disorder and Cannabis-Related Disorder NotOtherwise Specified (292.9); Cocaine-Related Disorders such as CocaineDependence (304.20), Cocaine Abuse (305.60), Cocaine Intoxication(292.89), Cocaine Withdrawal (292.0), Cocaine Intoxication Delirium,Cocaine-Induced Psychotic Disorder, Cocaine-Induced Mood Disorder,Cocaine-Induced Anxiety Disorder, Cocaine-Induced Sexual Dysfunction,Cocaine-Induced Sleep Disorder and Cocaine-Related Disorder NotOtherwise Specified (292.9); Hallucinogen-Related Disorders such asHallucinogen Dependence (304.50), Hallucinogen Abuse (305.30),Hallucinogen Intoxication (292.89), Hallucinogen Persisting PerceptionDisorder (Flashbacks) (292.89), Hallucinogen Intoxication Delirium,Hallucinogen-Induced Psychotic Disorder, Hallucinogen-Induced MoodDisorder, Hallucinogen-Induced Anxiety Disorder and Hallucinogen-RelatedDisorder Not Otherwise Specified (292.9); Inhalant-Related Disorderssuch as Inhalant Dependence (304.60), Inhalant Abuse (305.90), InhalantIntoxication (292.89), Inhalant Intoxication Delirium, Inhalant-InducedPersisting Dementia, Inhalant-Induced Psychotic Disorder,Inhalant-Induced Mood Disorder, Inhalant-Induced Anxiety Disorder andInhalant-Related Disorder Not Otherwise Specified (292.9);Nicotine-Related Disorders such as Nicotine Dependence (305.1), NicotineWithdrawal (292.0) and Nicotine-Related Disorder Not Otherwise Specified(292.9); Opioid-Related Disorders such as Opioid Dependence (304.00),Opioid Abuse (305.50), Opioid Intoxication (292.89), Opioid Withdrawal(292.0), Opioid Intoxication Delirium, Opioid-Induced PsychoticDisorder, Opioid-Induced Mood Disorder, Opioid-Induced SexualDysfunction, Opioid-Induced Sleep Disorder and Opioid-Related DisorderNot Otherwise Specified (292.9); Phencyclidine (orPhencyclidine-Like)-Related Disorders such as Phencyclidine Dependence(304.60), Phencyclidine Abuse (305.90), Phencyclidine Intoxication(292.89), Phencyclidine Intoxication Delirium, Phencyclidine-InducedPsychotic Disorder, Phencyclidine-Induced Mood Disorder,Phencyclidine-Induced Anxiety Disorder and Phencyclidine-RelatedDisorder Not Otherwise Specified (292.9); Sedative-, Hypnotic-, orAnxiolytic-Related Disorders such as Sedative, Hypnotic, or AnxiolyticDependence (304.10), Sedative, Hypnotic, or Anxiolytic Abuse (305.40),Sedative, Hypnotic, or Anxiolytic Intoxication (292.89), Sedative,Hypnotic, or Anxiolytic Withdrawal (292.0), Sedative, Hypnotic, orAnxiolytic Intoxication Delirium, Sedative, Hypnotic, or AnxiolyticWithdrawal Delirium, Sedative-, Hypnotic-, or Anxiolytic-PersistingDementia, Sedative-, Hypnotic-, or Anxiolytic-Persisting AmnesticDisorder, Sedative-, Hypnotic-, or Anxiolytic-Induced PsychoticDisorder, Sedative-, Hypnotic-, or Anxiolytic-Induced Mood Disorder,Sedative-, Hypnotic-, or Anxiolytic-Induced Anxiety Disorder Sedative-,Hypnotic-, or Anxiolytic-Induced Sexual Dysfunction, Sedative-,Hypnotic-, or Anxiolytic-Induced Sleep Disorder and Sedative-,Hypnotic-, or Anxiolytic-Related Disorder Not Otherwise Specified(292.9); Polysubstance-Related Disorder such as Polysubstance Dependence(304.80); and Other (or Unknown) Substance-Related Disorders such asAnabolic Steroids, Nitrate Inhalants and Nitrous Oxide.

In a further aspect therefore the present invention provides a method oftreating a condition for which modulation (especiallyantagonism/inhibition) of dopamine receptors (especially dopamine D₃receptors) is beneficial, which comprises administering to a mammal(e.g. human) in need thereof an effective amount of a compound offormula (I) or a pharmaceutically (i.e physiologically) acceptable saltthereof. Such conditions in particular include psychoses/psychoticconditions such as schizophrenia, and substance abuse.

The invention also provides the use of a compound of formula (I) or apharmaceutically acceptable salt thereof in the manufacture of amedicament for the treatment of a condition in a mammal for whichmodulation (especially antagonism/inhibition) of dopamine receptors(especially dopamine D₃ receptors) is beneficial.

The invention also provides a compound of formula (I) or apharmaceutically acceptable salt thereof for use in the treatment of acondition in a mammal for which modulation (especiallyantagonism/inhibition) of dopamine receptors (especially dopamine D₃receptors) is beneficial.

In one embodiment, D₃ antagonists according to the present invention areused in the treatment of psychoses such as schizophrenia or in thetreatment of substance abuse.

Thus, a still further aspect the invention provides a method of treatinga psychotic condition (e.g. schizophrenia) or substance abuse whichcomprises administering to a mammal (e.g. human) in need thereof aneffective amount of a compound of formula (I) as herein defined or apharmaceutically acceptable salt thereof.

Also provided is the use of a compound of formula (I) or apharmaceutically acceptable salt thereof in the manufacture of amedicament for the treatment of a psychotic condition (e.g.schizophrenia) or substance abuse in a mammal.

Also provided is a compound of formula (I) or a pharmaceuticallyacceptable salt thereof for use in the treatment of a psychoticcondition (e.g. schizophrenia) or substance abuse in a mammal.

Also provided is a compound of formula (I) or a pharmaceuticallyacceptable salt thereof for use as an active therapeutic substance in amammal, e.g. for use in the treatment of any of the conditions describedherein.

“Treatment” includes prophylaxis, where this is appropriate for therelevant condition(s).

For use in medicine, the compounds of the present invention are usuallyadministered as a standard pharmaceutical composition. The presentinvention therefore provides in a further aspect a pharmaceuticalcomposition comprising a compound of formula (I) or a pharmaceutically(i.e physiologically) acceptable salt thereof and a pharmaceutically(i.e physiologically) acceptable carrier. The pharmaceutical compositioncan be for use in the treatment of any of the conditions describedherein.

The compounds of formula (I) may be administered by any convenientmethod, for example by oral, parenteral (e.g. intravenous), buccal,sublingual, nasal, rectal or transdermal administration and thepharmaceutical compositions adapted accordingly.

The compounds of formula (I) and their pharmaceutically acceptable saltswhich are active when given orally can be formulated as liquids orsolids, for example syrups, suspensions or emulsions, tablets, capsulesand lozenges.

A liquid formulation will generally consist of a suspension or solutionof the compound or pharmaceutically acceptable salt in a suitable liquidcarrier(s) for example an aqueous solvent such as water, ethanol orglycerine, or a non-aqueous solvent, such as polyethylene glycol or anoil. The formulation may also contain a suspending agent, preservative,flavouring or colouring agent.

A composition in the form of a tablet can be prepared using any suitablepharmaceutical carrier(s) routinely used for preparing solidformulations. Examples of such carriers include magnesium stearate,starch, lactose, sucrose and cellulose.

A composition in the form of a capsule can be prepared using routineencapsulation procedures. For example, pellets containing the activeingredient can be prepared using standard carriers and then filled intoa hard gelatin capsule; alternatively, a dispersion or suspension can beprepared using any suitable pharmaceutical carrier(s), for exampleaqueous gums, celluloses, silicates or oils and the dispersion orsuspension then filled into a soft gelatin capsule.

Typical parenteral compositions consist of a solution or suspension ofthe compound or pharmaceutically acceptable salt in a sterile aqueouscarrier or parenterally acceptable oil, for example polyethylene glycol,polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.

Alternatively, the solution can be lyophilised and then reconstitutedwith a suitable solvent just prior to administration.

Compositions for nasal administration may conveniently be formulated asaerosols, drops, gels and powders. Aerosol formulations typicallycomprise a solution or fine suspension of the active substance in apharmaceutically acceptable aqueous or non-aqueous solvent and areusually presented in single or multidose quantities in sterile form in asealed container, which can take the form of a cartridge or refill foruse with an atomising device. Alternatively the sealed container may bea unitary dispensing device such as a single dose nasal inhaler or anaerosol dispenser fitted with a metering valve which is intended fordisposal once the contents of the container have been exhausted. Wherethe dosage form comprises an aerosol dispenser, it will contain apropellant which can be a compressed gas such as compressed air or anorganic propellant such as a fluorochloro-hydrocarbon. The aerosoldosage forms can also take the form of a pump-atomiser.

Compositions suitable for buccal or sublingual administration includetablets, lozenges and pastilles, wherein the active ingredient isformulated with a carrier such as sugar and acacia, tragacanth, orgelatin and glycerin.

Compositions for rectal administration are conveniently in the form ofsuppositories containing a conventional suppository base such as cocoabutter.

Compositions suitable for transdermal administration include ointments,gels and patches.

In one embodiment, the composition is in unit dose form such as atablet, capsule or ampoule.

Each dosage unit for oral administration contains for example from 1 to250 mg (and for parenteral administration contains for example from 0.1to 25 mg) of a compound of the formula (I) or a pharmaceuticallyacceptable salt thereof calculated as the free base.

The pharmaceutically acceptable compounds of the invention will normallybe administered in a daily dosage regimen (for an adult patient) of, forexample, an oral dose of between 1 mg and 500 mg, for example between 10mg and 400 mg, e.g. between 10 and 250 mg or an intravenous,subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, forexample between 0.1 mg and 50 mg, e.g. between 1 and 25 mg of thecompound of the formula (I) or a pharmaceutically acceptable saltthereof calculated as the free base, the compound being administered 1to 4 times per day. Suitably the compounds will be administered for aperiod of continuous therapy, for example for a week or more.

Biological Test Methods

Functional potency and intrinsic activity of compounds of this inventioncan be measured by the following GTPγS scintillation proximity assay(GTPγS-SPA). Cells used in the study are Chinese Hamster Ovary (CHO)Cells.

Cell Line CHO_D2 CHO_D3

Cell membranes are prepared as follows. Cell pellets are resuspended in10 volumes of 50 mM HEPES, 1 mM EDTA pH 7.4, using KOH. On the day thefollowing proteases are added to the buffer just prior to giving thehomogenisation buffer.

10⁻⁶M Leupeptin (Sigma L2884)−5000×stock=5 mg/ml in buffer

25 ug/ml Bacitracin (Sigma B0125)−1000×stock=25 mg/ml in buffer

1 mM PMSF−1000×stock=17 mg/ml in 100% ethanol

2×10⁻⁶M Pepstain A−1000×stock=2 mM in 100% DMSO

The cells are homogenised by 2×15 second bursts in a 1 litre GlassWaring blender in a class two biohazard cabinet. The resultingsuspension is spun at 500 g for 20 mins (Beckman T21 centrifuge: 1550rpm). The supernatant is withdrawn with a 25 ml pipette, aliquotted intopre-chilled centrifuge tubes and spun at 48,000 g to pellet membranefragments (Beckman T1270: 23,000 rpm for 30 mins). The final 48,000 gpellet is resuspended in Homogenisation Buffer, (4× the volume of theoriginal cell pellet). The 48,000 g pellet is resuspended by vortexingfor 5 seconds and homogenized in a dounce homogenizer 10-15 stokes. Theprep is distributed into appropriate sized aliquots, (200-1000 ul), inpolypropylene tubes and store at −80° C. Protein content in the membranepreparations is evaluated with the Bradford protein assay.

The final top concentration of test drug is 3 uM in the assay and 11points serial dilution curves 1:4 in 100% DMSO are carried out using aBiomek FX. The test drug at 1% total assay volume (TAV) is added to asolid, white, 384 well assay plate. 50% TAV of precoupled (for 90 minsat 4° C.) membranes, 5 μg/well, and Wheatgerm Agglutinin PolystyreneScintillation Proximity Assay beads (RPNQ0260, Amersham), 0.25 mg/well,in 20 mM HEPES pH 7.4, 100 mM NaCl, 10 mM MgCl₂, 60 μg/ml saponin and 30μM GDP is added. The third addition was a 20% TAV addition of eitherbuffer, (agonist format) or EC₈₀ final assay concentration of agonist,Quinelorane, prepared in assay buffer (antagonist format). The assay wasstarted by the addition of 29% TAV of GTPγ[³⁵S] 0.38 nM final (37MBq/ml, 1160 Ci/mmol, Amersham). After all additions assay plates arespun down for 1 min at 1,000 rpm. Assay plates are counted on a Viewlux,613/55 filter, for 5 min., between 2-6 hours after the final addition.

The effect of the test drug over the basal generates EC₅₀ value by aniterative least squares curve fitting programme, expressed in the tableas pEC₅₀ (i.e. −log EC₅₀). The ratio between the maximal effect of thetest drug and the maximal effect of full agonist, Quinelorane, generatesthe Intrinsic Activity (IA) value (i.e. IA=1 full agonist, IA<1 partialagonist). fpKi values of test drug are calculated from the IC₅₀generated by “antagonist format” experiment, using Cheng & Prusoffequation: fKi=IC₅₀/1+([A]/EC₅₀) where: [A] is the concentration of theagonist 5-HT in the assay and EC₅₀ is the 5-HT EC₅₀ value obtained inthe same experiment. fpKi is defined as −log fKi.

The compounds of the invention listed above have pKi values within therange of 7.0-10.5 at the dopamine D3 receptor. pKi results are onlyestimated to be accurate to about ±0.3-0.5.

The compounds of the invention listed above have a selectivity over D2greater than 30.

EXAMPLES

The invention is further illustrated by the following non-limitingexamples. Preparations 1 to 5 were carried out in analogy to thesynthetic route described in J. Med. Chem. 1981, 24, 481-490.

All temperatures refer to ° C. Infrared spectra were measured on a FT-IRinstrument. Compounds were analysed by direct infusion of the sampledissolved in acetonitrile into a mass spectra operated in positiveelectro spray (ES+) ionisation mode. Proton Magnetic Resonance (¹H-NMR)spectra were recorded at 400 MHz, chemical shifts are reported in ppmdownfield (d) from Me₄Si, used as internal standard, and are assigned assinglets (s), broad singlets (bs), doublets (d), doublets of doublets(dd), triplets (t), quartets (q) or multiplets (m).

Experimental vibrational circular dichroism (VCD) spectra were measuredusing a Chirall® VCD spectrometer operating in the 2000-800 cm-1frequency range. Spectra were measured at room temperature (23° C.)using a sealed transmission cell with barium fluoride windows and a pathlength of 100 microns. (Scan times varied from 60 to 120 minutes perisomer.) Sample solutions were typically prepared by dissolving 10milligrams of each enantiomer in 100 microliters of deutero-chloroform(CDCl₃). For ab initio assignments, VCD and unpolarized IR spectra werecalculated using the Gaussian 98 software package.1.

Optical rotations were measured using a (Perkin Elmer Model 241)polarimeter operating at 589 nm (Sodium source). Measurements were madeusing a 1 decimeter microcell thermostated at 23° C. Concentrations weretypically 10 mg/ml (c=0.01). For ab initio OR assignments, the DaltonQuantum Chemistry Program was used.

Column chromathography was carried out over silica gel (Merck AGDarmstaadt, Germany). The following abbreviations are used in the text:NBS=N-bromosuccinimide, Vitride=“Red-Al®”, HOBt=1-hydroxybenzotriazoleEtOAc=ethyl acetate, Et₂O=dietyl ether, DMF=N,N′-dimethylformamide,MeOH=methanol, TFA=trifluoroacetic acid,tetrahydrofuran=tetrahydrofuran, IPA=isopropanol, TEA=triethylamine,DCC=1,3-dicyclohexylcarbodiimide, SCX=strong cation exchanger, Tlcrefers to thin layer chromatography on silica plates, and dried refersto a solution dried over anhydrous sodium sulphate, r.t. (RT) refers toroom temperature, Rt=retention time, DMSO=dimethyl sulfoxide.

Preparation 1: Methyl bromo(4-methoxyphenyl)acetate

To a mixture of methyl 4-methoxyphenylacetate (20 g, 0.11 mol) and NBS(0.11 mol) in CCl₄ (0.2 l) were added 3 drops of 48% HBr and thismixture was heated to reflux for 8 h. The cooled solution was filteredthrough a pad of silica gel and the filtrate was evaporated in vacuo togive 29 g of the title compound as pale yellow oil, which was used inthe subsequent step without further purification.

NMR (¹H, CDCl₃): δ 7.3 (d, 2H), 6.8 (d, 2H), 5.1 (s, 1H), 3.8 (s, 3H),3.5 (s, 3H).

Preparation 2: Dimethyl1-(4-methoxyphenyl)-1,2-cyclopropanedicarboxylate

To a stirred slurry of NaH (4.4 g, 60% in mineral oil) in anhydrous Et₂O(0.3 l) was added methanol (10.3 mL) followed by a solution of bromoester obtained in Prep. 1 methyl bromo(4-methoxyphenyl)acetate (29 g) inmethyl acrylate (19.8 mL) (for examples starting from an ethylphenylacetate derivative ethanol and ethyl acrylate were used,respectively) and methanol (3 mL) at 0° C., over a 30 min. The mixturewas stirred at 25° C. for 24 h and then unreacted NaH was decomposedwith 3 mL methanol. Water was added (75 mL), the organic phaseseparated, dried over Na₂SO₄ and filtered. Volatiles were evaporated invacuo to give 31.5 g of the title compound as an oil, which was used inthe subsequent step without further purification.

NMR (¹H, CDCl₃): δ 7.3 (d, 2H), 6.8 (d, 2H), 3.77 (s, 3H), 3.73 (s, 3H),3.64 (s, 3H), 2.18 (dd, 1H), 2.05 (dd, 1H), 1.46 (dd, 1H). MS (m/z):265.4 [MH]⁺.

Preparation 3: 1-(4-Methoxyphenyl)-1,2-cyclopropanedicarboxylic acid

A mixture of diester obtained in Prep. 2 (31.5 g) and KOH (13.5 g) in1:1 EtOH:H₂O (240 mL) was heated at reflux for 6 h and then concentratedto half the original volume. The aqueous solution was extracted withEt₂O, chilled in ice, and then made acidic with 25 mL of 12N HCl. Whitecrystalline product was collected by filtration and dried under vacuo togive 12.8 of the title compound (overall yield from methylbromo(4-methoxyphenyl)acetate: 50%).

NMR (¹H, DMSO): δ 12.5 (bs, 2H), 7.25 (d, 2H), 6.85 (d, 2H), 3.7 (s,3H), 2.0 (dd, 1H), 1.85 (dd, 1H), 1.38 (dd, 1H). MS (m/z): 235.0 [M-H]⁻.

Preparation 4:(1R,5S/1S,5R)-1-[4-(Methoxy)phenyl]-3-azabicyclo[3.1.0]hexane-2,4-dione

A mixture of 12.8 g of the diacid obtained in Preparation 3 and 6.5 g ofurea in 300 mL of m-xylene was heated at reflux for 8 h and thenconcentrated to dryness in vacuo. The crude was purified by columnchromatography (AcOEt:cyclohexane=1 (?):10 to 4:6) to give 5.5 g of thetitle compound (y=46%).

MS (m/z): 218.1 [MH]⁺.

Preparation 5:(1R,5S/1S,5R)-[4-(Methoxy)phenyl]-3-azabicyclo[3.1.0]hexane

To a stirred slurry of 5.5 g of the imide obtained in Preparation 4 in170 mL of toluene was slowly added 45 mL of Vitride (3.4 M in toluene)under N₂. This solution was stirred at reflux for 2 h. To the cooledsolution was cautiously added aqueous NaOH (10 M, 40 mL) and the organiclayer was washed with two portions of water and dried over Na₂SO₄. Thissolution was filtered, and the filtrate was evaporated in vacuo to give4.8 g of the title compound (y=100%).

NMR (¹H, CDCl₃): δ 7.10 (d, 2H), 6.82 (d, 2H), 3.77 (s, 3H), 3.35-2.98(m, 4H), 2.58 (dd, 1H), 0.87 (dd, 1H), 0.78 (dd, 1H), NH not observed.MS (m/z): 190.1 [MH]⁺.

Preparation 6: (1R,5S/1S,5R)-1-(4-Bromophenyl)-3-azabicyclo[3.1.0]hexane

To 20 mL of 1M BH₃-tetrahydrofuran, stirred at 0° C. under N₂, wasslowly added a solution of 1.32 g (5 mmol) of(1R,5S/1S,5R)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione,prepared in analogy to Preparation 4, in 20 mL of dry tetrahydrofuran.This solution was stirred at room temperature for 15 min and then warmedon a steam bath for 1 h. The solution was then cooled in an ice bath,2.5 mL of 6 M HCl was added cautiously, and the solvent was removed invacuo. The residual material was combined with 12.5 mL of 5 M NaOH andthe mixture was extracted with ether. The ether extract was washed twicewith water, dried over Na₂SO₄ and filtered to give 1.19 g of the titlecompound (y=100%).

NMR (¹H, CDCl₃): δ 7.35 (d, 2H), 7.02 (d, 2H), 3.25-2.96 (m, 4H), 1.63(dd, 1H), 1.55 (dd, 1H), 1.30 (dd, 1H), NH not observed. MS (m/z): 238.1[MH]⁺, 1Br.

Preparation 7:(1R,5S/1S,5R)-4-[3-(Trifluoroacetyl)-3-azabicyclo[3.1.0]hex-1-yl]benzonitrile

Trifluoroacetic anhydride (0.21 mL) was added to a solution of4-[3-azabicyclo[3.1.0]hex-1-yl]benzonitrile (280 mg, prepared in analogyto the method described in Preparation 5), and triethylamine (0.25 mL)in dichloromethane (15 mL) at 0° C. The reaction mixture was allowed towarm to room temperature over 2 h, then washed with saturated NaHCO₃,the organic layer dried and evaporated to give 269 mg of the titlecompound.

MS (m/z): 281.2 [MH]⁺.

Preparation 8:(1R,5S/1S,5R)-4-[3-(Trifluoroacetyl)-3-azabicyclo[3.1.0]hex-1-yl]benzaldehyde

A mixture of4-[3-(trifluoroacetyl)-azabicyclo[3.1.0]hex-1-yl]benzonitrile (283 mg),Ni—Al alloy (450 mg), formic acid (3.9 mL) and water (1.1 mL) wasstirred at 80° C. for 3 h. The reaction mixture was cooled to roomtemperature and filtered. The filtrate was extracted with ethyl acetateand the organic phase washed with NaHCO₃, dried over Na₂SO₄ andevaporated in vacuo to give 195 mg of the title compound as yellow oil.

MS (m/z): 284.2 [MH]⁺.

Preparation 9:(1R,5S/1S,5R)-4-[3-(Trifluoroacetyl)-3-azabicyclo[3.1.0]hex-1-yl]benzaldehydeoxime

To a solution of4-[3-(trifluoroacetyl)-3-azabicyclo[3.1.0]hex-1-yl]benzaldehyde (195 mg)in 5 mL of pyridine was added hydroxylamine hydrochloride (57.5 mg) andthe mixture was stirred for 3 h at room temperature. The solvent wasevaporated, the crude dissolved in ethyl acetate and the organic phasewashed with 10% aqueous Na₂CO₃ and brine, dried over Na₂SO₄ andevaporated in vacuo to give 225 mg of the title compound as yellow oil.

MS (m/z): 299.2 [MH]⁺.

Preparation 10:(1R,5S/1S,5R)-4-[3-(Trifluoroacetyl)-3-azabicyclo[3.1.0]hex-1-yl]-N-hydroxybenzenecarboximidoylchloride

To a solution of4-[3-(trifluoroacetyl)-(3-azabicyclo[3.1.0]hex-1-y]benzaldehyde oxime(0.69 mmol) in 3.5 mL of dimethylformamide was added portion wiseN-chlorosuccinimide (97 mg) at 0° C. After stirring for 1.5 h at 40° C.the solvent was evaporated. The crude product was dissolved in diethylether/dichloromethane (4/1) and the organic phase washed with water,dried over Na₂SO₄ and concentrated in vacuo to give 243 mg of the titlecompound as a brown oil.

Preparation 11:(1R,5S/1S,5R)-1-[4-(5-Methyl-3-isoxazolyl)phenyl]-3-(trifluoroacetyl)-3-azabicyclo[3.1.0]hexane

To a solution of4-[3-(trifluoroacetyl)-3-azabicyclo[3.1.0]hex-1-yl)-N-hydroxybenzenecarboximidoylchloride (0.69 mmol) in 6 mL of chloroform triethylamine (0.24 mL) and2-chloro propene (0.29 mL) were added and the reaction stirred for 18 hat room temperature. The solution was washed with water, dried overNa₂SO₄ and volatiles evaporated in vacuo. The crude was purified bycolumn chromatography (AcOEt:cyclohexane=1:10 to 4:6) to give 180 mg ofthe title compound.

MS (m/z): 337.2 [MH]⁺.

Preparation 12:(1R,5S/1S,5R)-1-[4-(5-Methyl-3-isoxazolyl)phenyl]-3-azabicyclo[3.1.0]hexane

A mixture of1-[4-(5-methyl-3-isoxazolyl)phenyl]-3-(trifluoroacetyl)-3-azabicyclo[3.1.0]hexane(0.54 mmol) and K₂CO₃ (296 mg) in methanol (5 mL) and water (5 mL) wasstirred for 4 h at 50° C. The solvent was evaporated in vacuo and theproduct treated with dichloromethane/isopropanol 1/1 and filtered. Thefiltrate was dried over Na₂SO₄ and volatiles evaporated in vacuo to give105 mg of the title compound (y=81%).

MS (m/z): 241.2 [MH]⁺.

Preparation 13:5-{5-[(3-Chloropropyl)thio]-4-methyl-4H-1,2,4-triazol-3-yl}-2-methylquinoline

To4-methyl-5-(2-methyl-5-quinolinyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione(3.6 g, prepared in analogy to the method described in WO200240471) inethanol (60 mL) containing 1-bromo-3-chloropropane (2.0 mL) wascarefully added with stirring sodium hydride (0.60 g, 60% in petrolium).The mixture was heated at reflux for 45 min. Volatiles were evaporatedin vacuo and the residue submitted to column chromatography(EtOAc—acetone gradient). The material thus obtained was precipitatedfrom hot EtOAc (20 mL) by adding petroleum ether (40-60, 50 mL), cooledand collected by filtration to provide the title compound as colourlesscrystals (2.1 g).

NMR (¹H, CDCl₃): δ 8.18 (d, 1H), 8.12 (d, 1H), 7.76 (t, 1H), 7.55 (d,1H), 7.30 (d, 1H), 3.75 (t, 2H), 3.50 (t, 2H), 3.40 (s, 3H), 2.76 (s,3H), 2.37 (m, 2H).

Preparation 14:3-[(3-Chloropropyl)thio]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole

Ethyl-2-chloroacetoacetate (1 wt; 1 eq., 1000 g) was aged with formamide(0.68 vol; ca. 2.8 eq.) and the resulting solution was heated to 120° C.After 5 hours the mixture was allowed to cool to room temperature andallowed to age under nitrogen over night. The mixture was treated withNaOH (3 M, 6 vol, reaction moderately exothermic) and stirred at roomtemperature for 4 hours. Ethyl acetate (6 vol) was added and the phasesallowed to separate. The organic layer was discarded while the aqueouswas acidified with conc. (32%) aqueous HCl to pH 2 (ca. 2.0 vol). Aprecipitate started to form. The suspension was treated with AcOEt (8vol) and vigorously stirred until the bulk of the precipitate haddissolved. The aqueous phase was further extracted with AcOEt twice (6vol each) and the combined organic layers distilled to low volume (againa suspension was observed at low volume). Fresh AcOEt (8 vol) was addedand the mixture evaporated to dryness. The collected solid was placed inthe oven at 40° C. over night under reduced pressure to give4-methyl-1,3-oxazole-5-carboxylic acid (498 g, 64.5%).

This material (498 g, 1 wt) was dissolved in dry tetrahydrofuran (5vol), under nitrogen, cooled to 0° C. DCC (1.62 wt, 1 eq) was addedportionwise followed by HOBt (1.07 wt, 1 eq). The mixture was warmed to25±2° C. and stirred for 30 min. 4-Methyl-3-thiosemicarbazide (0.83 wt,1 eq) was then added and the mixture further stirred for 2 h at 25±2° C.The mixture was filtered and the cake was washed with freshtetrahydrofuran (1 vol) and dried on the filter for a few hours. Thecake was suspended in 1 M aqueous NaOH (13 vol) and heated to 70° C. for30 min. After this time, the mixture was cooled to 25±2° C. and a solidwas removed by filtration. The cake was washed with 1 M aqueous NaOH (10vol). The combined mother liquors were cooled to 0° C. and acidified toca. pH 5 with HCl (aqueous, 16%; NOTE: keep temperature while adding HClbelow +10° C.). The suspended product was isolated by filtration washingwith water (2×3 vol). The cake was dried at 40° C. for 18 h in highvacuum to obtain4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione(respectively a tautomeric form thereof; 290 g, 37%). NaOEt (21%solution in EtOH, 2.08 vol, 1.1 eq) was added to EtOH (20 vol) undernitrogen atmosphere.4-Methyl-5-(4-methyl-1,3-oxazol-5-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione(respectively a tautomeric form thereof; 290 g, 1 wt) was added in oneportion and the resulting mixture stirred at 25±2° C. until a clearsolution was obtained. Then 1-bromo-3-chloropropane (0.54 vol, 1.1 eq)was added and the solution stirred at 40° C. for 24 h then cooled to 25°C. After filtration water (20 vol) was added and the ethanolic phase wasremoved by vacuum distillation (internal temperature ˜40° C.). Themixture was extracted with EtOAc (41 vol). The aqueous layer was removedand the organic phase was evaporated to dryness. Dichloromethane (4 vol)was added. The organic solution is purified through a short silica gelcolumn (18 wt of silica), eluting with EtOAc (200 vol) to give the titlecompound as a solid foam (267.64 g, 66%).

NMR (¹H, CDCl₃): δ 7.90 (s, 1H), 3.70 (s, 5H), 3.40 (t, 2H), 2.52 (s,3H), 2.30 (m, 2H).

Preparation 15: 3-[4-(Trifluoromethyl)phenyl]-1H-pyrrole-2,5-dione

A mixture of hydrochloric acid (37%, 285 mL) and water (190 mL) wasadded to 4-(trifluoromethyl)aniline (150 g, 116 mL) at room temperaturewith vigorous stirring and the formed precipitate was allowed to stirfor further 30 minutes. Temperature was reduced to 0° C. and sodiumnitrite (70.6 g) in 180 mL of water was added dropwise to the stirredsuspension. At the end of diazotisation, a clear yellow solution wasobtained. Maleimide (180 g) in acetone (1.1 l) was added dropwise at 0°C. and then the pH of the solution was adjusted to 3-3.5 by addingsodium acetate. Copper (II) chloride (18.8 g) was added to thevigorously stirred mixture. After a few minutes a gas started to develop(conspicuous foaming). The reaction mixture was allowed to stir at 0° C.for 1 h and overnight at room temperature.

Acetone was removed in vacuo, the residue was filtered and driedovernight in vacuo to give the title compound (155 g) as a light brownsolid (y=63%).

MS (m/z): 242.2 [MH]⁺.

Preparation 16:(1R,5S/1S,5R)-1-[4-(Trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]-hexane-2,4-dione

Milled sodium hydroxide (40 g) was added in small portions to a stirredsolution of trimethylsulfoxonium iodide (219 g) in DMSO (anhydrous, 2l). The resulting mixture was allowed to stir at room temperature for1.5 h.

3-[4-(Trifluoromethyl)phenyl]-1H-pyrrole-2,5-dione (Preparation 15, 120g) dissolved in DMSO (anhydrous, 0.5 l) was then added dropwise and theresulting mixture was allowed to stir at room temperature for 20minutes. Temperature was then reduced to 0° C. and NH₄Cl (aqueoussaturated solution, 2 l) was slowly added, followed by Et₂O (1 l). Afterseparation of the two phases, the aqueous layer was repeatedly extractedwith Et₂O (3×1 l). Combined organic layers were washed with brine (2×1l) and then dried over Na₂SO₄. Evaporation of the solvent gave a lightbrown solid which was suspended in 1 l of dichloromethane and 1 l ofcyclohexane. The mixture was allowed to stir at room temperature for 45minutes and then filtered to give the title compound (116 g) as whitesolid (y=71%).

MS (m/z): 256.1 [MH]⁺.

Preparation 17:(1R,5S/1S,5R)-1-[4-(Trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]-hexane

Borane (1M in tetrahydrofuran, 1.4 l) was charged into a 5 l reactorunder N₂ and cooled at 0° C.(1R,5S/1S,5R)-1-[4-(Trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane-2,4-dione(Preparation 16, 101 g) dissolved in tetrahydrofuran (anhydrous, 1 l)was then added dropwise with vigorous stirring whereby the temperaturewas constantly kept below 5° C. and gas evolution was monitored. At theend of the addition the resulting mixture was allowed to stir at 0° C.for 1 h and then at room temperature overnight.

The mixture was then cooled to 0° C. and methanol (200 mL) followed byhydrochloric acid (6 M solution, 0.8 l) were cautiously added monitoringgas evolution. tetrahydrofuran was then removed in vacuo, the residuewas cooled to 0° C. and sodium hydroxide (5 M solution) was added untilpH 9-10 had been reached. The aqueous layer was extracted with Et₂O (3×1l). Removal of solvent in vacuo gave the title compound (140 g) ascolorless oil.

MS (m/z): 228.1 [MH]⁺.

Preparation 18:(1S,5R)-1-[4-(Trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane

(S)-(+)-Mandelic acid (94 g) was added in portions to a stirred solutionof (1R,5S/1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane(Preparation 17, 140 g) in 1.4 l of tetrahydrofuran. The resultingmixture was stirred at room temperature for 2 h until a whiteprecipitate was formed. The mixture was then warmed up to refluxtemperature, stirred for 45 minutes and then slowly cooled down to roomtemperature. The white solid was collected by filtration and dried invacuo. This material was recrystallised 4 times from tetrahydrofuran (10volumes) to give 32.5 g of a white solid. This material was thensuspended in sodium hydroxide (1M solution, 400 mL) and Et₂O (400 mL)and allowed to stir at room temperature until complete dissolution.After separation of the two phases, the aqueous layer was extractedagain with Et₂O (3×250 mL). Combined organic layers were washed withsodium hydroxide (1M solution, 3×200 mL) and then dried over Na₂SO₄.Evaporation of solvent in vacuo gave the title compound (19 g) as whitesolid (y=37%).

The absolute configuration of the optical isomers was assigned usingcomparative VCD (vibrational circular dichroism) and OR (opticalrotation) analyses.

The configuration of the title compound was assigned by comparing itsexperimental VCD spectrum and observed specific rotation to the dataobserved for (1S,5R)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane(see Preparation 48) as the reference sample. The assignment of theabsolute configuration of the title compound was confirmed by a singlecrystal X-ray structure obtained from a crystal of(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane,(S)-(+)-mandelic acid salt. Both, analysis based on the knownconfiguration of the (S)(+)-mandelic acid and on the basis of anomalousdispersion effects confirmed the assignment of the title compound asbeing (1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane.

NMR (¹H, CDCl₃): δ 7.51 (d, 2H), 7.25 (d, 2H), 3.20 (d, 1H), 3.0-3.1 (m,3H), 1.69 (m, 1H), 0.8-1.0 (m, 2H), NH not observed. MS (m/z): 228.1[MH]⁺.

Analytical Chromatography

Column: chiralcel OD 10 um, 250×4.6 mmMobile phase: A: n-Hexane; B: Isopropanol+0.1% Isopropyl amineGradient: isocratic 2% BFlow rate: 1 mL/minUV wavelength range: 200-400 nmAnalysis time 25 minret. time (min) % a/a16.5 0.4 (1R,5S)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane21.7 99.6 title compound

Specific Optical Rotation: [α]_(D)=−10° (CDCl₃, T=20° C., c≅0.004 g/0.8mL).

Preparation 19:3-{(1S,5R)-1-[4-(Trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}-1-butanol

To a suspension of(1S,5R)-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane(Preparation 18, 100 mg) in tetrahydrofuran (1.1 mL),4-hydroxy-2-butanone (0.66 mmol), acetic acid (0.66 mmol) and NaBH(OAc)₃(0.88 mmol) were added. The mixture was stirred at room temperature for2 h. After addition of NaOH (1M), the solvent was eliminated undervacuo, the residue was dissolved in ethyl acetate and the organic layerwas washed with H₂O and dried over Na₂SO₄. This solution wasconcentrated in vacuo to give 130 mg of the title compound which wasused without further purification.

MS (m/z): 300 [MH]⁺.

Preparation 20:(1S,5R)-3-(3-Chloro-1-methylpropyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane

To a solution of3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}-1-butanol(Preparation 19, 130 mg) in chloroform (4 mL), thionyl chloride (0.87mmol) was added and the mixture was stirred at room temperature for 6 h.After addition of NaOH (1 M), dichloromethane was added and the organiclayer was washed with Brine and dried over Na₂SO₄. The solution wasconcentrated in vacuo and the crude product purified by flashchromatography (ethyl acetate:cyclohexane=5:95) to give 106 mg of thetitle compound.

MS (m/z): 318 [MH]⁺.

Preparation 21:1-{5-[(1S,5R/1R,5S)-3-Azabicyclo[3.1.0]hex-1-yl)-2-(methyloxy)phenyl}ethanone

The title compound was prepared in 32 mg yield from1-[4-(methyloxy)phenyl]-3-(trifluoroacetyl)-3-azabicyclo[3.1.0]hexane(94 mg) as described for preparation 34.

MS (m/z): 232 [MH]+. HPLC: condition 1, Rt=3.393 min.

Preparation 22:(1S,5R/1R,5S)-1-(4-Chlorophenyl)-3-azabicyclo[3.1.0]hexane

The title compound was prepared in 230 mg yield from commerciallyavailable methyl 4-chlorophenylacetate (1 g, 5.5 mmol) following themethods described in preparations 1, 2, 3, 4, 6.

MS (m/z): 194 [MH]+.

Preparation 23:(1S,5R/1R,5S)-1-(4-Fluorophenyl)-3-azabicyclo[3.1.0]hexane

The title compound was prepared in 160 mg yield from commerciallyavailable methyl 4-fluorophenylacetate (1 g, 6 mmol) following themethods described in preparations 1, 2, 3, 4, 6.

MS (m/z): 178 [MH]+.

Preparation 24:(1S,5R/1R,5S)-1-(3-Chlorophenyl)-3-azabicyclo[3.1.0]hexane

The title compound was prepared in 1.25 g yield from commerciallyavailable methyl 3-chlorophenylacetate (5 g, 27 mmol) following themethods described in preparations 1, 2, 3, 4, 5.

MS (m/z): 194 [MH]+. HPLC: condition 1, Rt=3.469 min.

Preparation 25:(1S,5R/1R,5S)-1-(3-Fluorophenyl)-3-azabicyclo[3.1.0]hexane

The title compound was prepared in 1.97 g yield from commerciallyavailable methyl 3-fluorophenylacetate (5 g, 29.7 mmol) following themethods described in preparations 1, 2, 3, 4, 5.

MS (m/z): 178 [MH]+.

Preparation 26:(1S,5R/1R,5S)-1-[3-(Methyloxy)phenyl]-3-azabicyclo[3.1.0]hexane

The title compound was prepared in 1.2 g yield from commerciallyavailable methyl 3-methoxyphenylacetate (5 g, 27.7 mmol) following themethods described in preparations 1, 2, 3, 4, 5.

MS (m/z): 190 [MH]+. HPLC: condition 1, Rt=3.219 min.

Preparation 27:(1S,5R/1R,5S)-1-[2-Methyl-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane

The title compound was prepared in 71 mg yield from commerciallyavailable 2-methyl-4-(trifluoromethyl)aniline (1 g, 5.7 mmol) followingthe methods described in preparations 15, 16, 17.

MS (m/z): 242 [MH]+.

Preparation 28: Methyl bromo{4-[(trifluoromethyl)oxy]phenyl}acetate

To a solution of 4-trifluoromethoxyphenylacetic acid (5 g, 23 mmol) incarbon tetrachloride oxalyl chloride (25 mmol) and two drops of DMF wereadded at 0° C. After stirring the solution at room temperature for 1 h,NBS (25 mmol) and few drops of 48% HBr were added and the mixture washeated to reflux for 4 h. The solution was allowed to cool, MeOH (5 mL)was added and the mixture was stirred at room temperature for 1 h.

After filtration through a pad of silica gel, the filtrate wasevaporated in vacuo to give 7.2 g of the title compound as yellow foam,which was used in the subsequent step without further purification.

MS (m/z): 314 [MH]+.

Preparation 29:(1S,5R/1R,5S)-1-{4-[(Trifluoromethyl)oxy]phenyl}-3-azabicyclo[3.1.0]hexane

The title compound was prepared in 1.2 g yield from methyl3-trifluoromethoxyphenylacetate (Preparation M, 23 mmol) following themethods described in preparations 2, 3, 4, 5.

MS (m/z): 244 [MH]+. HPLC: condition 1, Rt=3.942 min.

Preparation 30:(1S,5R/1R,5S)-1-[3-(Trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane

The title compound was prepared in 1.5 g yield from commerciallyavailable 3-trifluoromethylphenylacetic acid (5 g, 24.5 mmol), followingthe methods described in preparations 28, 2, 3, 4, 5.

MS (m/z): 228 [MH]+. HPLC: condition 1, Rt=3.665 min.

Preparation 31:(1R,5S/1S,5R)-1-(3-Bromophenyl)-3-azabicyclo[3.1.0]hexane

The title compound was prepared in 1.6 g yield from commerciallyavailable 3-bromophenylacetic acid (5 g, 23.2 mmol), following themethods described in preparations 28, 2, 3, 4, 6.

MS (m/z): 239 [MH]+. HPLC: condition 1, Rt=3.528 min.

Preparation 32: (1S,5R)-1-(4-Bromophenyl)-3-azabicyclo[3.1.0]hexane

(S)(+)-Acetyl mandelic acid (3.22 g) was added in portions to a stirredsolution of (1R,5S/1S,5R)-1-[4-bromophenyl]-3-azabicyclo[3.1.0]hexane(Preparation 6, 3.96 g) in 80 mL of IPA. The resulting mixture wasstirred at room temperature for 2 h until a white precipitate wasformed. The mixture was then warmed up to reflux temperature, stirredfor 45 minutes and then slowly allowed to cool to room temperature. Thewhite solid was collected by filtration and dried in vacuo. Thismaterial was recrystallised 4 times from IPA (10 volumes) to give 2.3 gof a white solid.

This material was then suspended in sodium hydroxide (1M aqueoussolution, 400 mL) and Et₂O (400 mL) and allowed to stir at roomtemperature until complete dissolution. After separation of the twophases, the aqueous layer was extracted again with Et₂O (3×250 mL).Combined organic layers were washed with sodium hydroxide (1M solution,3×200 mL) and then dried over Na₂SO₄. Evaporation of solvent in vacuogave the title compound (1.24 g) as white solid.

The absolute configuration of the optical isomers was assigned asdescribed for Preparation 18.

The assignment of the absolute configuration of the title compound wasconfirmed by a single crystal X-ray structure obtained from a crystal of(1S,5R)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]hexane, (S)-(+)-O-acetylmandelic acid salt. Both, analysis based on the known configuration ofthe (S)(+)-acetyl mandelic acid and on the basis of anomalous dispersioneffects confirmed the assignment of the title compound as being(1S,5R)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]hexane.

NMR (¹H, CDCl₃): δ 7.43 (d, 2H), 7.09 (d, 2H), 3.25 (d, 1H), 3.15 (m,2H), 3.06 (d, 1H), 1.71 (m, 1H), 0.95 (dd, 1H), 0.89 (t, 1H), NH notobserved. MS (m/z): 239 [MH]⁺.

Analytical Chromatography

Column: chiralcel OD 5 μm, 250×4.6 mmMobile phase: A: n-Hexane; B: Isopropanol+0.1% Isopropyl amineGradient: isocratic 2% BFlow rate: 1 mL/minUV wavelength range: 200-400 nmAnalysis time 25 minRet. time 22.3 min, purity >99% a/aSpecific Optical Rotation: [α]_(D)=−86° (CDCl₃, T=20° C., c=0.0053 g/0.8mL).

Preparation 33:(1R,5S/1S,5R)-1-[2-(Trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane

The title compound was prepared in 53 mg yield from commerciallyavailable methyl [2-(trifluoromethyl)phenyl]acetate (944 mg) followingthe methods described in preparations 1, 2, 3, 4 and 5.

MS (m/z): 228 [MH]⁺.

Preparation 34:1-[4-[(1R,5S/1S,5R)-3-Azabicyclo[3.1.0]hex-1-yl]-2-(methyloxy)phenyl]ethanone

To a mixture of AlCl₃ (2 eq) in 1,2-dichloroethane (anhydrous, 9 mL) at0° C. was added acetyl chloride (1.05 eq). The reaction mixture wasstirred at 0° C. for 15 min and a solution of1-[3-(methyloxy)phenyl]-3-(trifluoroacetyl)-3-azabicyclo[3.1.0]hexane(1.1 g, obtained in analogy to the method described in preparation 7from 1-[3-(methyloxy)phenyl]-3-azabicyclo[3.1.0]hexane) in1,2-dichloroethane (anhydrous, 9 mL) was added. The reaction mixture wasstirred at RT for 1.5 h. HCl (1 M, 4 mL) was added followed by water (20mL) and the mixture was extracted with dichloromethane. The organiclayer was washed with saturated aqueous NaHCO₃ and dried over Na₂SO₄.The solution was filtered and the filtrate was concentrated in vacuo.The crude product was purified by flash chromatography(cyclohexanes:EtOAc 6:4) to give 593 mg as a colourless liquid of theprotected amine. 143 mg of the protected amine was dissolved in MeOH:H₂O (3 mL:3 mL) and K₂CO₃ (4 eq) was added stirring the mixture at 50°C. for 2.5 h. The reaction mixture was extracted with dichloromethaneand the organic layer was washed with saturated aqueous NaHCO₃ and driedover Na₂SO₄. The solution was filtered and the filtrate was concentratedin vacuo to give the title compound as a white solid (88 mg).

MS (m/z): 232 [MH]⁺.

HPLC: Conditions 1 Analytical Column: Supelcosil ABZ+Plus 33×4.6 mm, 3μm

Mobile phase: A: H2O+0.1% HCOOH, B: CH3CNGradient: 0% (B) for 1 min, from 0% (B) to 95% (B) in 5 min, 95% (B) for2 minFlow rate: 1 mL/minUV wavelength: 285 nm, band width 130 nmMass range: 100-1000 amu

Ionization: ES+ R_(t) 2.971 min Preparation 35:1-[4-[(1R,5S/1S,5R)-3-Azabicyclo[3.1.0]hex-1-yl)-2-(methyloxy)phenyl]-1-propanone

The title compound was prepared using propionyl chloride in place ofacetyl chloride, in 106 mg yield from 147 mg of protected amine obtainedin 705 mg from1-[3-(methyloxy)phenyl]-3-(trifluoroacetyl)-3-azabicyclo[3.1.0]hexane(1.07 g) as described for preparation 34.

MS (m/z): 246 [MH]⁺.

HPLC: Conditions 1 R_(t) 3.249 min Preparation 36:1(1R,5S/1S,5R)-[2-Fluoro-5-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane

The title compound was prepared in 112 mg yield from2-fluoro-5-(trifluoromethyl)aniline (1.09 g) following the proceduresreported for preparations 37 and 6.

NMR (¹H, CDCl₃): δ 7.45 (m, 2H), 7.1 (m, 1H), 3.2 (m, 2H), 3.05 (m, 2H),1.7 (m, 1H), 0.95 (m, 1H), 0.9 (m, 1H), NH not observed. MS (m/z): 246[MH]⁺.

Preparation 37: 1(1R,5S/1S,5R)-[2-Fluoro-4-(trifluoromethyl)phenyl]-3azabicyclo[3.1.0]hexane-2,4-dione

To a slurry of maleimide (1.7 eq), anhydrous CuCl₂ (1.2 eq) andtert-butyl nitrite (1.5 eq) in CH₃CN (35 mL) at 0° C. a solution of2-fluoro-4-(trifluoromethyl)aniline (16.3 g) in CH₃CN (6.5 mL) was addeddropwise. The reaction mixture was stirred at room temperature for 1 hand HCl (10%, aqueous, 196 mL) was added. The mixture was extracted withEtOAc, the organic layer was washed with saturated aqueous NaCl anddried over Na₂SO₄. The solution was filtered and the filtrate wasconcentrated in vacuo. By NMR analysis the crude mixture resulted a 1:4mixture of the arylated maleimide hydrogen chloride adduct (component A)and unreacted maleimide (component B).

A DMSO (140 mL) solution of this crude product was added dropwise to apreformed solution of trimethylsulfoxonium iodide (2 eq with respect tocomponent A plus 2 eq with respect to component B) in anhydrous DMSO(412 mL) to which NaH (3 eq with respect to component A plus 2 eq withrespect to component B) had been added portionwise. The reaction mixturewas stirred for 30 min and AcOH (2 eq) was added followed by water. Thereaction mixture was extracted with Et₂O and then with EtOAc, thecombined organic layers were washed with saturated aqueous NaCl anddried over Na₂SO₄. The solution was filtered and the filtrate wasconcentrated in vacuo. The crude product obtained was triturated withwater and then with cyclohexanes to give the title compound as lightbrown solid (5.98 g).

NMR (¹H, CDCl₃): δ 7.55-7.3 (m, 3H), 2.8-2.7 (m, 1H), 2.1 (m, 1H), 2.0(m, 1H), NH not observed. MS (m/z): 274 [MH]⁺.

Preparation 38(1R,5S/1S,5R)-1-[2-Fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane

To a solution of(1R,5S/1S,5R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo-[3.1.0]hexane-2,4-dione(2.6 g) in anhydrous tetrahydrofuran (56 mL), BH₃ in tetrahydrofuran (1M, 4 eq) was added at 0° C. The reaction mixture was stirred at 65° C.for 24 h, cooled to RT and MeOH was added until gas evolution ceased.Solvent was removed in vacuo, MeOH was added (200 mL) p-tolueneulfonicacid (3 eq) was added and the reaction mixture was stirred at 65° C. for6 h, the reaction mixture was cooled to room temperature and a saturatedsolution of K₂CO₃ (1.7 eq) was added. The mixture was extracted withdichloromethane, the organic layer was washed with saturated aqueousNaCl and dried over Na₂SO₄. The solution was filtered and the filtratewas concentrated in vacuo to give the title compound as colourless oil(2.1 g).

NMR (¹H, CDCl₃): δ 7.2-7.4 (m, 3H), 3.2 (m, 2H), 3.1 (m, 2H), 1.8 (m,1H), 0.8 (m, 2H), NH not observed. MS (m/z): 246 [MH]⁺.

Preparation 39:(1S,5R)-1-[2-Fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane

(1R)-(−)-10-Camphorsulfonic acid (4.19 g) was added in portions to astirred solution of(1R,5S/1S,5R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane(4.4 g) in CH₃CN (44 mL). The resulting mixture was stirred at roomtemperature for 20 min until a white precipitate formed. The mixture wasthen warmed up to reflux temperature, stirred for 45 minutes and thenslowly allowed to cool to room temperature. The white solid wascollected by filtration and dried in vacuo. This material wasrecrystallised 2 times from CH₃CN (25 mL per g solid) to give 1.57 g ofa white solid.

This material was then suspended in sodium hydroxide (1M solution, 1.1eq) and dichloromethane (100 mL) and allowed to stir at room temperatureuntil complete dissolution. After separation of the two phases, theaqueous layer was extracted again with dichloromethane. The combinedorganic layers were washed with sodium hydroxide and then dried overNa₂SO₄. Evaporation of solvent in vacuo gave the title compound (874 mg)as colorless liquid.

Analytical Chromatography

Column: chiralcel OD 10 μm, 250×4.6 mmMobile phase: A: n-Hexane; B: Isopropanol+0.1% Isopropyl amineGradient: isocratic 2% BFlow rate: 0.8 mL/minUV wavelength range: 200-400 nm

Analysis

ret. time (min) % a/a17.18 >99.5(1S,5R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane

Preparation 40:(1S,5R)-3-(3-Chloropropyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane

To a solution of(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (1.00 g)in dry tetrahydrofuran (5 mL), diisopropylethylamine (2.4 mL) and1-bromo-3-chloropropane (3.7 mL) were added and the resulting mixturewas heated at reflux for 3 hours. After cooling at room temperature itwas diluted with ethyl acetate (30 mL) washed twice with a saturatedsolution of NH₄Cl in water (20 mL) and once with a saturated solution ofNaHCO₃ in water (20 mL), dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. The crude product was purified by silica gelchromatography eluting with cyclohexane/EtOAc 7:3 to give the titlecompound as a colourless oil (1.26 g).

NMR (¹H, CDCl₃): δ 7.50 (d, 2H) 7.19 (d, 2H), 3.59 (t, 2H), 3.33 (d,1H), 3.09 (d, 1H), 2.58 (m, 2H), 2.66 (dd, 1H), 2.46 (dd, 1H), 1.92 (m,2H), 1.74 (m, 1H), 1.67 (t, 1H), 0.81 (dd, 1H). MS (m/z): 304 [MH]⁺.

Preparation 41:(1S,5R)-3-(3-Chloropropyl)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane

To a solution of(1S,5R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane(300 mg) in dry tetrahydrofuran (3 mL), diisopropylethylamine (0.65 mL)and 1-bromo-3-chloropropane (1.01 mL) were added and the resultingmixture was refluxed for 3 hours.

After cooling at room temperature it was diluted with ethyl acetate (15mL) washed twice with a saturated solution of NH₄Cl in water (10 mL) andonce with a saturated solution of NaHCO₃ in water (10 mL), dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudeproduct was purified by chromatography (silica gel) eluting withcyclohexane/EtOAc 6:4 to give the title compound as yellow oil (345 mg).

NMR (¹H, CDCl₃): δ 7.24 (d, 2H), 7.16 (t, 1H), 3.51 (t, 2H), 3.18 (dd,1H), 3.03 (d, 1H), 2.54 (t, 2H), 2.48 (dd, 1H), 2.37 (d, 1H), 1.83 (m,2H), 1.69 (m, 1H), 1.34 (t, 1H), 0.70 (dd, 1H). MS (m/z): 322 [MH]⁺.

Preparation 42:(1R,5S/1S,5R)-1-[3-Fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane

The title compound was prepared in 338 mg yield from3-fluoro-4-(trifluoromethyl)aniline (2 g) following the proceduresreported for Preparations 37 and 6.

NMR (¹H, CDCl₃): δ 7.5 (m, 1H), 6.9 (m, 2H), 3.3-3.0 (m, 4H), 1.7 (m,1H), 0.95 (m, 2H), NH not observed. MS (m/z): 246 [MH]⁺.

Preparation 43:(1R,5S/1S,5R)-1-[4-(Methyloxy)phenyl]-3-(trifluoroacetyl)-3-azabicyclo[3.1.0]hexane

The title compound was prepared in 1.80 g yield (95%) as a colorless oilfrom (1R,5S/1S,5R)-1-[4-(methoxy)phenyl]-3-azabicyclo[3.1.0]hexane (1.25g) in analogy to the method described in Preparation 7.

MS (m/z): 286 [MH]⁺.

Preparation 44:1-{2-(Methyloxy)-5-[(1R,5S/1S,5R)-3-(trifluoroacetyl)-3-azabicyclo[3.1.0]hex-1-yl]phenyl}ethanone and1-{2-hydroxy-5-[(1R,5S/1S,5R)-3-(trifluoroacetyl)-3-azabicyclo[3.1.0]hex-1-yl]phenyl}ethanone

To a suspension of AlCl₃ (12.6 mmol) in dry 1,2-dichloroethane (16 mL)at 0° C. acetyl chloride (6.6 mmol) was added and the mixture wasstirred at this temperature for 15 min. A solution of(1R,5S/1S,5R)-1-[4-(methyloxy)phenyl]-3-(trifluoroacetyl)-3-azabicyclo[3.1.0]hexane(1.81 g, 6.3 mmol) in 1,2-dichloroethane (16 mL) was then added. Thereaction mixture was allowed to stir at 0° C. for 15 min and overnightat room temperature. 1 M aqueous HCl was then added and the mixture wasextracted with dichloromethane. The organic phase was washed with 5%NaHCO₃ and water, dried over Na₂SO₄ and concentrated in vacuo. The twoproducts were separated by flash chromatography (cyclohexane/ethylacetate from 95/5 to 80/20) to give 965 mg of1-{2-(methyloxy)-5-[(1R,5S/1S,5R)-3-(trifluoroacetyl)-3-azabicyclo[3.1.0]hex-1-yl]phenyl}ethanone(48%) and 266 mg of1-{2-hydroxy-5-[(1R,5S/1S,5R)-3-(trifluoroacetyl)-3-azabicyclo[3.1.0]hex-1-yl]phenyl}ethanone(18%) as yellow oils.

MS (m/z): 328 [MH]⁺,1-{2-(methyloxy)-5-[(1R,5S/1S,5R)-3-(trifluoroacetyl)-3-azabicyclo[3.1.0]hex-1-yl]phenyl}ethanone;312 [M-H]⁻,1-{2-hydroxy-5-[(1R,5S/1S,5R)-3-(trifluoroacetyl)-3-azabicyclo[3.1.0]hex-1-yl]phenyl}ethanone.

Preparation 45:1-[5-[(1R,5S/1S,5R)-3-Azabicyclo[3.1.0]hex-1-yl]-2-(methyloxy)phenyl]ethanone

The title compound was prepared in 624 mg yield (91%) as a colorless oilfrom1-{2-(methyloxy)-5-[(1R,5S/1S,5R)-3-(trifluoroacetyl)-3-azabicyclo[3.1.0]hex-1-yl]phenyl}ethanone(965 mg) in analogy to the method described in Preparation 12.

MS (m/z): 232 [MH]⁺.

Preparation 46:1-{5-[(1R,5S/1S,5R)-3-Azabicyclo[3.1.0]hex-1-yl]-2-hydroxyphenyl}ethanone

The title compound was prepared in 151 mg yield (82%) as a colorless oilfrom1-{2-hydroxy-5-[(1R,5S/1S,5R)-3-(trifluoroacetyl)-3-azabicyclo[3.1.0]hex-1-yl]phenyl}ethanone(266 mg) in analogy to the method described in Preparation 12.

MS (m/z): 216 [M-H]⁻.

Preparation 47:(1S,5R/1R,5S)-1-(4-Bromophenyl)-3-(3-chloropropyl)-3-azabicyclo[3.1.0]hexane

To a solution of racemic(1S,5R/1R,5S)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]hexane (0.12 g) indry tetrahydrofuran (2 mL), diisopropylethylamine (0.22 mL) and1-bromo-3-chloropropane (0.062 mL) were added and the resulting mixturewas heated at reflux for 3 hours. After cooling to room temperature thesolvent was removed in vacuo and the resulting crude oil was taken up indichloromethane (10 mL). This solution was then washed twice with asaturated solution of NH₄Cl in water (5 mL), dried over anhydrous Na₂SO₄and concentrated under reduced pressure. The crude product was purifiedpassing the sample through a 2 g silica cartridge (Varian) with agradient elution from cyclohexane to cyclohexane/EtOAc 7:3, to give thetitle compound as a colourless oil (0.10 g).

NMR (¹H, DMSO): δ 7.45 (d, 2H), 7.10 (d, 2H), 3.65 (t, 2H), 3.30 (d,1H), 3.00 (d, 1H), 2.55 (t, 2H), 2.45 (m, 1H), 2.40 (dd, 1H), 1.85 (m,2H), 1.80 (m, 1H), 1.30 (t, 1H), 0.70 (m, 1H). MS (m/z): 314, 316, 318[MH]⁺.

Preparation 48:(1R,5S/1S,5R)-1-(3,4-Dichlorophenyl)-3-azabicyclo[3.1.0]hexane

The crude title compound was prepared in 0.36 g yield from commerciallyavailable methyl 3,4-dichlorophenylacetate (1 g, 4.57 mmol) followingthe methods described in preparations 1, 2, 3, 4, 6.

The title compound was separated to give the separated enantiomers bypreparative chromatography using a chiral column chiralcel AD 10 um,250×21 mm, eluent A: n-hexane; B: isopropanol+0.1% isopropyl amine,gradient isocratic 2% B, flow rate 7 mL/min, detection UV at 200-400 nm.Retention times given were obtained using an analytical HPLC using achiral column chiralcel AD 5 um, 250×4.6 mm, eluent A: n-hexane; B:isopropanol+0.1% Isopropyl amine, gradient isocratic 2% B, flow rate 1.2mL/min, detection UV at 200-400 nm.

Enantiomer 1, (1R,5S)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane,was recovered in 20 mg yield as white solid from the racemate (60 mg).Rt.=41 min.

Enantiomer 2, (1S,5R)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane,was recovered in 28 mg yield as white solid from the racemate (60 mg).Rt.=43.4 min.

The absolute configuration of(1S,5R)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane was assignedusing ab initio VCD and ab initio OR analyses.

Specific Optical Rotation of(1S,5R)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane: [α]_(D)=−67.9°(CDCl₃, T=20° C., c≅0.01 g/mL).

NMR (¹H, CDCl₃): δ 7.35 (d, 1H), 7.27 (s, 1H), 7.02 (dd, 1H), 3.25 (d,1H), 3.13 (bm, 2H), 3.06 (d, 1H), 1.71 (m, 1H), 0.93 (m, 2H), NH notobserved. MS (m/z): 228 [MH]⁺.

Preparation 49:1-(Phenylmethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole

Diisopinocampheylborane was prepared following the procedure reported inJ. Org. Chem. 1984, 49, 945-947.2-[(1Z)-3-Chloro-1-(chloromethyl)-1-propen-1-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(previously described in Tetrahedron Lett. 1993, 34, 4827-4828) wasprepared following the general procedure reported in Tetrahedron Lett.1989, 30, 2929, using 1,4-dichloro-2-butyne. The material thus obtainedwas further converted following the procedure reported in Synlett 2002,5, 829-831. This latter procedure was modified in that isolation of thetitle product was achieved (rather than by distillation) by extractionof a solution of the crude reaction products in acetonitrile withcyclohexane, to provide the title compound (containing ˜10% in moles ofbenzylamine) after evaporation of the volatiles from the cyclohexanephase.

Preparation 50:2-[1-(Phenylmethyl)-2,5-dihydro-1H-pyrrol-3-yl]-5-(trifluoromethyl)pyridine

To a solution of 2-bromo-5-(trifluoromethyl)pyridine (4.42 mmol) in drytetrahydrofuran (45 mL)1-(phenylmethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole(3.4 mmol), tetrakis(triphenylphosphine)palladium(0) (0.196 mmol) andcesium fluoride (13.2 mmol) were added at room temperature. Theresulting mixture was stirred at 80° C. for 1.5 hours. After coolingsolvent was evaporated under reduced pressure and the residue waspartitioned between dichloromethane (25 mL) and sodium hydroxyde (15 mL,1M). The organic phase was evaporated under reduced pressure. The crudeproduct was purified by silica gel column chromatography(AcOEt:cyclohexane=1:10 to 4:6) to give 0.33 g of the title compound(y=24%).

NMR (¹H, CDCl₃): δ 9.8 (s, 1H), 7.85 (dd, 1H), 7.5-7.2 (m, 6H), 6.7 (s,1H), 3.95 (m, 2H), 3.9 (s, 2H), 3.75 (m, 2H). MS (m/z): 305 [MH]⁺.

Preparation 51:2-[1-(Phenylmethyl)-2,5-dihydro-1H-pyrrol-3-yl]-6-(trifluoromethyl)pyridine

2-[1-(Phenylmethyl)-2,5-dihydro-1H-pyrrol-3-yl]-6-(trifluoromethyl)pyridinewas prepared in analogy to the method described in Preparation 50 in0.56 g (y=42%) as an oil.

NMR (¹H, CDCl₃): δ 7.7 (t, 1H), 7.85 (dd, 1H), 7.4-7.1 (m, 6H), 6.5 (s,1H), 3.90 (sb, 2H), 3.8 (s, 2H), 3.6 (m, 2H). MS (m/z): 305 [MH]⁺.

Preparation 52:3-(Phenylmethyl)-1-[5-(trifluoromethyl)-2-pyridinyl]-3-azabicyclo[3.1.0]hexane

To a slurry of sodium hydride (83 mg) and trimethylsulfoxonium iodide(0.46 g) DMSO (anhydrous, 3 mL) was added dropwise (gas evolution). Theresulting mixture was allowed to stir at room temperature for 0.5 h. Asolution of2-[1-(phenylmethyl)-2,5-dihydro-1H-pyrrol-3-yl]-5-(trifluoromethyl)pyridine(330 mg) in DMSO (anhydrous, 6 mL) was added at room temperature. After1 h a saturated solution of ammonium chloride (4 mL) was added and themixture extracted with dichloromethane (2×10 mL). Volatiles from theorganic phase were evaporated under reduced pressure, the residuecharged onto an SCX column and eluted with MeOH followed by MeOH/NH₃0.25 M. The methanole/ammonia fractions were concentrated under reducedpressure to give 0.31 g of the title compound (y=89%).

NMR (¹H, CDCl₃): δ 8.78 (s, 1H), 8.03 (dd, 1H), 7.32 (m, 5H), 7.25 (m,1H), 3.66 (dd, 2H), 3.25 (d, 1H), 2.96 (d, 1H), 2.80 (d, 1H), 2.46 (sb,1H), 2.05 (q, 1H), 1.58 (m, 1H), 1.22 (m, 1H). MS (m/z): 317 [MH]⁺.

Preparation 53:3-(Phenylmethyl)-1-[6-(trifluoromethyl)-2-pyridinyl]-3-azabicyclo[3.1.0]hexane

3-(Phenylmethyl)-1-[6-(trifluoromethyl)-2-pyridinyl]-3-azabicyclo[3.1.0]hexanewas prepared in analogy to the method described in Preparation 52 (0.46g, 79%) as an oil.

NMR (¹H, CDCl₃): δ 7.7 (t, 1H), 7.4 (d, 1H), 7.35 (m, 5H), 7.2 (d, 1H),3.7 (s, 2H), 3.4 (d, 1H), 3.1 (d, 1H), 2.85 (d, 1H), 2.55 (m, 1H), 2.1(m, 1H), 1.7 (m, 1H), 1.3 (m, 1H). MS (m/z): 317 [MH]⁺.

Preparation 54:1-[5-(Trifluoromethyl)-2-pyridinyl]-3-azabicyclo[3.1.0]hexane

3-(Phenylmethyl)-1-[5-(trifluoromethyl)-2-pyridinyl]-3-azabicyclo[3.1.0]hexanewas dissolved in ethanol (15 mL), hydrochloric acid (3M, 0.76 mL) wasadded followed, in inert atmosphere, by Pd/C 10% w/w (120 mg). After 20h under a hydrogen atmosphere (1 atm) the mixture was filtered. Solventwas removed under reduced pressure. A saturated solution of sodiumbicarbonate was added (10 mL) and the mixture extracted with diethylether (2×10 mL) to provide the title compound (0.14 g, 81%) afterevaporation of volatiles.

NMR (¹H, DMSO-d⁶): δ 8.7 (s, 1H), 7.8 (d, 1H), 7.15 (d, 1H), 3.4-3.2(dd, 2H), 3.1 (m, 2H), 2.05 (m, 1H), 1.4 (m, 1H), 1.05 (t, 1H).

Preparation 55:2-Fluoro-4-[1-(phenylmethyl)-2,5-dihydro-1H-pyrrol-3-yl]benzonitrile

The title compound was prepared in analogy to the method described inPreparation 50 in 0.44 g (y=31%) as an oil.

NMR (¹H, CDCl₃): δ 7.55 (t, 1H), 7.4-7.2 (m, 5H), 7.2 (d, 1H), 7.1 (d,1H), 6.4 (bs, 1H), 3.9 (s, 2H), 3.8 (m, 2H), 3.75 (m, 2H). MS (m/z): 279[MH]⁺.

Preparation 56:2-Fluoro-4-[3-(phenylmethyl)-3-azabicyclo[3.1.0]hex-1-yl]benzonitrile

The title compound was prepared in analogy to the method described inPreparation 52 in 0.39 g (y=84%) as an oil.

NMR (¹H, CDCl₃): δ 7.41 (t, 1H), 7.25-7.15 (m, 5H), 6.85-6.8 (dd, 2H),3.64-3.56 (dd, 2H), 3.19 (dd, 1H), 3.01 (dd, 1H), 2.53 (dd, 1H), 2.47(dd, 1H), 1.73 (q, 1H), 1.67 (m, 1H), 0.81 (m, 1H). MS (m/z): 293 [MH]⁺.

Preparation 57:1-[3-Fluoro-4-(1H-pyrrol-1-ylmethyl)phenyl]-3-azabicyclo[3.1.0]hexane

To a solution of{[4-(3-azabicyclo[3.1.0]hex-1-yl)-2-fluorophenyl]methyl}aminedihydrochloride in methanol/tetrahydrofuran (anhydrous, 1/1, 5 mL),which was prepared in analogy to the method described in Preparation 54starting from 1.1 mmol of2-fluoro-4-[3-(phenylmethyl)-3-azabicyclo[3.1.0]hex-1-yl]benzonitrileand used without further purification, a solution of2,5-bis(methyloxy)tetrahydrofuran (2.53 mmol), H₂SO₄ (4.4 mmol) inmethanol/tetrahydrofuran (anhydrous, 1/1, 5 mL) was added dropwise over5 min at room temperature. After standing over night at room temperaturea saturated solution of NaHCO₃ was slowly added, extraction with 2×15 mLof dichloromethane followed by preparative HPLC purification provided 14mg of titled compound as an oil (y=5%).

NMR (¹H, CDCl₃): δ 6.88-6.82 (m, 3H), 6.67 (t, 2H), 6.14 (t, 2H), 5.04(s, 2H), 3.21 (d, 1H), 3.1 (d, 1H), 3.09 (d, 1H), 3.01 (d, 1H), 1.67 (m,1H), 0.88 (m, 2H). MS (m/z): 257 [MH]⁺.

Preparation 58:(1R,5S/1S,5R)-3-(3-Chloropropyl)-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane

The title compound was prepared in 522 mg yield (84%) as a colorless oilfrom(1R,5S/1S,5R)-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane(584 mg) in analogy to the method described in Preparation 40.

NMR (¹H, CDCl₃): δ 8.47 (s, 1H), 7.55 (m, 2H), 3.59 (t, 2H), 3.33 (d,1H), 3.09 (d, 1H), 2.6 (m, 3H), 2.52 (dd, 1H), 1.92 (m, 2H), 1.78 (m,1H), 0.85 (m, 1H), 0.81 (dd, 1H). MS (m/z): 305 [MH]⁺.

Preparation 59:5-[(1R,5S/1S,5R)-3-(3-Chloropropyl)-3-azabicyclo[3.1.0]hex-1-yl]-2-methyl-1,3-benzothiazole

The title compound was prepared in 480 mg yield (84%) as a colorless oilfrom5-[(1R,5S/1S,5R5)-3-azabicyclo[3.1.0]hex-1-yl]-2-methyl-1,3-benzothiazole(374 mg) in analogy to the method described in Preparation 40.

NMR (¹H, CDCl₃): δ 7.70 (m, 2H), 7.11 (d, 1H), 3.59 (t, 2H), 3.38 (d,1H), 3.09 (d, 1H), 2.8 (s, 3H), 2.66 (m, 3H), 2.53 (dd, 1H), 1.95 (m,2H), 1.74 (m, 1H), 1.44 (t, 1H), 0.83 (dd, 1H).

MS (m/z): 307 [MH]⁺.

Preparation 60:1(1R,5S/1S,5R)-[3-Fluoro-5-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane-2,4-dione

To a slurry of maleimide (1.8 eq), anhydrous CuCl₂ (1.2 eq) andtert-butyl nitrite (1.5 eq) in CH₃CN (5 mL) at 0° C. a solution of3-fluoro-5-(trifluoromethyl)aniline (2.2 g) in CH₃CN (4 mL) was addeddropwise. The reaction mixture was stirred at room temperature for 2 hand HCl (aqueous 6 M, 30 mL) was added. The mixture was extracted withEtOAc, the organic layer dried over Na₂SO₄. The solution was filteredand the filtrate was concentrated in vacuo. The filtered was trituratedwith water and dried in vacuo

A DMSO (10 mL) solution of this crude product was added dropwise to apreformed solution of trimethylsulfoxonium iodide (2 eq) in anhydrousDMSO (20 mL) to which NaH (15 eq) had been added portionwise. Thereaction mixture was stirred for 30 min and water was added followed bya satured solution of NH₄Cl (until pH 6.5). The reaction mixture wasextracted with Et₂O, the combined organic layers were washed withsaturated aqueous NaCl and dried over Na₂SO₄. The solution was filteredand the filtrate was concentrated in vacuo. The crude product obtainedwas triturated with cyclohexane to give the title compound as lightgreen solid (1.02 g).

NMR (¹H, CDCl₃): δ 7.4-7.20 (m, 3H), 2.85-2.75 (m, 1H), 2.0 (m, 1H),1.85 (m, 1H), NH not observed. MS (m/z): 274 [MH]⁺.

Preparation 61:(1R,5S/1S,5R)-1-[3-Fluoro-5-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane

The title compound was prepared in 650 mg yield from(1R,5S/1S,5R)-1-[3-fluoro-5-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane-2,4-dionefollowing the procedure reported for Preparation 38.

NMR (¹H, CDCl₃): δ 7.05-7.40 (m, 3H), 3.1-3.3 (m, 4H), 1.7 (m, 1H), 0.9(m, 2H), NH not observed. MS (m/z): 246 [MH]⁺.

Preparation 62:(1R,5S/1S,5R)-1-[2-Fluoro-3-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane

The title compound was prepared in 947 mg yield from2-fluoro-3-(trifluoromethyl)aniline (3 g) following the proceduresreported for Preparations 60 and 38.

NMR (¹H, CDCl₃): δ 7.2 (m, 2H), 6.9 (m, 1H), 3.0-2.7 (m, 4H), 1.6 (m,1H), 0.7 (m, 2H);

MS (m/z): 246 [MH]⁺.

Preparation 63:(1R,5S/1S,5R)-1-[4-(Methyloxy)-5-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane

The title compound was prepared in 430 mg yield from4-(methyloxy)-5-(trifluoromethyl)aniline (2.2 g) following theprocedures reported for Preparations 60 and 38.

NMR (¹H, CDCl₃): δ 7.4-7.3 (m, 2H), 6.9 (m, 1H), 3.9 (s, 3H), 3.2-3.0(m, 4H), 1.9 (s, 1H), 1.65 (m, 1H), 0.8 (m, 2H). MS (m/z): 258 [MH]⁺.

Preparation 64:(1R,5S/1S,5R)-1-(4-Chloro-2-fluorophenyl)-3-azabicyclo[3.1.0]hexane

The title compound was prepared in 360 mg yield from 4-chloro-2-fluoroaniline (1.87 g) following the procedures reported for Preparations 60and 38.

NMR (¹H, CDCl₃): δ 7.2-7.0 (m, 3H), 3.2-3.0 (m, 4H), 2.0 (s, 1H), 1.75(m, 1H), 0.8 (m, 2H). MS (m/z): 212 [MH]⁺.

Preparation 65:(1R,5S/1S,5R)-1-{3-[(Trifluoromethyl)oxy]phenyl}-3-azabicyclo[3.1.0]hexane

The title compound was prepared in 600 mg yield from3-trifluoromethyloxy aniline (2.65 g) following the procedures reportedfor Preparations 60 and 38.

NMR (¹H, CDCl₃): δ 7.3-7 (m, 4H), 3.3-3.0 (m, 4H), 1.8 (s, 1H), 1.75 (m,1H), 0.95 (m, 2H); MS (m/z): 212 [MH]⁺.

Preparation 66:(1R,5S/1S,5R)-1-(2-Fluoro-4-methylphenyl)-3-azabicyclo[3.1.0]hexane

The title compound was prepared in 148 mg yield from 2-fluoro-4-methylaniline (2.18 g) following the procedures reported for Preparations 60and 38.

NMR (¹H, CDCl₃): δ 7.2 (m, 1H), 6.85 (m, 2H), 3.2-2.9 (m, 4H), 2.25 (s,3H), 1.75 (s, 1H), 1.65 (m, 1H), 0.9 (m, 2H); MS (m/z): 192 [MH]⁺.

Preparation 67:(1R,5S/1S,5R)-1-[3-Chloro-4-(methyloxy)phenyl]-3-azabicyclo[3.1.0]hexane

The title compound was prepared in 60 mg yield from 2-chloro-4-methylaniline (2.36 g) following the procedures reported for Preparations 60and 38.

NMR (¹H, CDCl₃): δ 7.15-7 (m, 2H), 6.85 (m, 1H), 3.85 (s, 3H), 3.2-2.9(m, 4H), 1.8-1.6 (m, 2H), 0.75 (m, 2H); MS (m/z): 224 [MH]⁺.

Preparation 68: (1R,5S/1S,5R)-1,1-Dimethylethyl1-(4-bromophenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a stirred solution of(1R,5S/1S,5R)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]hexane (Preparation6, 1.3 g) in dichloromethane (20 mL) at room temperature, triethylamine(0.99 mL) and bis(1,1-dimethylethyl)dicarbonate were added. Stirring wascontinued over 6 h, then the reaction mixture was concentrated undervacuum and the crude product treated with diethyl ether and water. Theorganic phase was washed with saturated ammonium chloride solution,dried over sodium sulphate and the solvent evaporated under vacuum togive a crude product that was purified by chromatography over silica gel(cyclohexane/ETOAC 9/1) affording the title compound (1.68 g, 91%).

MS (m/z): 282.1 [MH-C₄H₈]⁺, 1Br.

Preparation 69: (1R,5S/1S,5R)-1,1-Dimethylethyl1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a stirred solution of (1R,5S/1S,5R)-1,1-dimethylethyl1-(4-bromophenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (2 g) in DMF(30 mL), at RT, bis(pinacolate)di boron (2.25 g), potassium acetate(1.75 g) and PdCl₂(dppf) (0.15 g) were subsequently added. The reactionmixture was heated at 85° C. for 1.5 h, poured into water and extractedtwice with diethylether, and the organic phase was washed with brine anddried over sodium sulphate. The solvent was evaporated under vacuum andthe crude product purified by chromatography over silica gel(cyclohexane/ETOAC 9/1) affording the title compound as a white solid(2.1 g, 92%).

MS (m/z): 330.3 [MH-C₄H₈]⁺, 1Br.

Preparation 70: (1R,5S/1S,5R)-1,1-Dimethylethyl1-(3-bromophenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

The title compound was prepared in 94% yield as a white solid in analogyto the method described for Preparation 68 starting from(1R,5S/1S,5R)-1-(3-bromophenyl)-3-azabicyclo[3.1.0]hexane (7.4 g).

MS (m/z): 282.1 [MH-C₄H₈]⁺, 1Br.

Preparation 71: (1R,5S/1S,5R)-1,1-Dimethylethyl1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

The title compound was prepared in 84% yield as a white solid in analogyto the method described for Preparation 69 starting from(1R,5S/1S,5R)-1,1-dimethylethyl1-(3-bromophenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (2.5 g).

MS (m/z): 330.3 [MH-C₄H₈]⁺, 1Br.

Preparation 72:(1R,5S/1S,5R)-1-[4-(2,4-Dimethyl-1,3-thiazol-5-yl)phenyl]-3-azabicyclo[3.1.0]hexane

To a stirred solution of (1R,5S/1S,5R)-1,1-dimethylethyl1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(0.3 g) in tetrahydrofuran (12 mL), at RT and under a nitrogenatmosphere, 5-bromo-2,4-dimethyl-1,3-thiazole (0.22 g), cesium fluoride(0.47 g) and tetrakis-(triphenylphosphin)-palladium(0) (0.06 g) weresubsequently added. The reaction mixture was heated at 80° C. for 4 hand the solvent evaporated under vacuum. The crude product was treatedwith diethyl ether and saturated aqueous ammonium chloride solution, theorganic phase was washed with brine, dried over sodium sulphate andconcentrated under vacuum. The crude product was purified bychromatography over silica gel (cyclohexane/ETOAC 8/1). The purifiedproduct was then dissolved in CH₂Cl₂ (10 mL) and trifluoroacetic acidwas added (4 mL). After 2 h the reaction mixture was treated with solidsodium carbonate and the solvent evaporated. The residue was treatedwith water and extracted with CH₂Cl₂, the organic phase washed withbrine, dried over sodium sulphate and evaporated to give the titlecompound (0.1 g, 34%).

MS (m/z): 271.2 [MH]⁺.

Preparation 73:(1R,5S/1S,5R)-1-{4-[6-(Trifluoromethyl)-2-pyridinyl]phenyl}-3-azabicyclo[3.1.0]hexane

The title compound was prepared in analogy to the method described forPreparation 72 (using 2-bromo-6-(trifluoromethyl)pyridine) in 60% yield.

MS (m/z): 305.3 [MH]⁺.

Preparation 74:(1R,5S/1S,5R)-1-[4-(3,5-Dimethyl-4-isoxazolyl)phenyl]-3-azabicyclo[3.1.0]hexane

To a stirred solution of (1R,5S/1S,5R)-1,1-dimethylethyl1-(4-bromophenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.37 g) intoluene (5 mL) and ethyl alcohol (2 mL), at RT and under a nitrogenatmosphere, (3,5-dimethyl-4-isoxazolyl)boronic acid (0.25 g),tetrakis-(triphenylphosphin)-palladium(0) (0.03 g) and a saturatedsolution of potassium carbonate (2 mL) were subsequently added. Thereaction mixture was heated at 88° C. for 2 h, and the solventsevaporated under vacuum. The crude product was treated with diethylether and water, the organic phase washed with brine, dried over sodiumsulphate, concentrated under vacuum and extracted twice with ether. Thesolvent was evaporated and the crude product purified by chromatographyover silica gel (cyclohexane/ETOAC 8/1). The recovered product was thendissolved in CH₂Cl₂ (10 mL) and trifluoroacetic acid was added (4 mL).After 3 h the reaction mixture was treated with solid sodium carbonateand the solvent evaporated. The residue was treated with water andextracted with CH₂Cl₂, the organic phase washed with brine, dried oversodium sulphate and evaporated to give the title compound (0.12 g, 45%).

MS (m/z): 255.2 [MH]⁺.

Preparation 75:(1R,5S/1S,5R)-1-[3-(2,4-Dimethyl-1,3-thiazol-5-yl)phenyl]-3-azabicyclo[3.1.0]hexane

The title compound was prepared in analogy to the method described forPreparation 72, using (1R,5S/1S,5R)-1,1-dimethylethyl1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-azabicyclo[3.1.0]hexane-3-carboxylateintermediate 4), in 50% yield.

MS (m/z): 271.3 [MH]⁺.

Preparation 76:(1R,5S/1S,5R)-1-[3-(5-Methyl-2-thienyl)phenyl]-3-azabicyclo[3.1.0]hexane

The title compound was prepared in analogy to the method described forPreparation 72, using (1R,5S/1S,5R)-1,1-dimethylethyl1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-azabicyclo[3.1.0]hexane-3-carboxylateintermediate 4), in 55% yield.

MS (m/z): 256.2 [MH]⁺.

Preparation 77:5-(2,4-Dimethyl-1,3-oxazol-5-yl)-4-methyl-2,4-dihydro-3H-1,2,4-triazole-3-thione

2,4-Dimethyl-1,3-oxazole-5-carboxylic acid (0.8 g),N-methylhydrazinecarboxamide (0.6 g), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.09 g), HOBt (0.038 g) and triethylamine(0.86 ml) were dissolved, under nitrogen, in dry DMF (15 ml) at roomtemperature. The mixture was stirred overnight, then DMF was removedunder vacuum. NaOH (0.75M, 10 ml) was added and mixture was heated at80° C. for 3 h. The reaction mixture was cooled to 0° C. and acidifiedto ca. pH 5 with HCl (aqueous, 37%). The suspended product was isolatedby filtration, washing with water (2×3 ml). The cake was dried at roomtemperature overnight under vacuum to give the title compound in a 3:2mixture with 2,4-dimethyl-1,3-oxazole-5-carboxylic acid as a solid foam(0.68 g, 57% yield).

NMR (¹H, CDCl₃): δ 3.80 (s, 3H), 2.60 (s, 3H), 2.40 (s, 3H), NH/SH notobserved.

Preparation 78:3-[(3-Chloropropyl)thio]-5-(2,4-dimethyl-1,3-oxazol-5-yl)-4-methyl-4H-1,2,4-triazole

The product mixture from Preparation 77 was suspended in EtOH (10 ml).NaOEt (21% solution in EtOH, 1.14 ml) was added followed by1-bromo-3-chloropropane (0.41 ml), the solution stirred at 90° C. for 45min, then cooled to 25° C. Acetic acid (0.1 eq.) was added than solventwas removed under vacuum. The solid was purified by silica gel columnchromatography, eluting with cyclohexane/EtOAc to give the titlecompound as a solid foam (0.44 g, 54% yield).

NMR (¹H, CDCl₃): δ 3.70 (t+s, 5H), 3.35 (t, 2H), 2.50 (s, 3H), 2.4 (s,3H), 2.30 (m, 2H).

MS (m/z): 287 [MH]⁺.

Example 15-[5-({3-[(1R,5S/1S,5R)-1-(4-Methoxyphenyl)-3-azabicyclo[3.1.0]hex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazol-3-yl]-2-methylquinolinehydrochloride

A mixture of(1R,5S/1S,5R)-1-[4-(methoxy)phenyl]-3-azabicyclo[3.1.0]hexane(Preparation 5, 42 mg),5-{5-[(3-chloropropyl)thio]-4-methyl-4H-1,2,4-triazol-3-yl}-2-methylquinoline(0.26 mmol), Na₂CO₃ (0.44 mmol) and NaI (0.22 mmol) in DMF (anhydrous,0.4 mL) was heated at 60° C. for 24 h. After elimination of the solventunder vacuo, the residue was dissolved in ethyl acetate and the organiclayer was washed with saturated aqueous NaHCO₃ and dried over Na₂SO₄.This solution was filtered and the filtrate was concentrated in vacuo.The crude was purified by flash chromatography (dichloromethane to 10%MeOH in dichloromethane) to give 65 mg of the free base of the titlecompound. To a solution of this material in dichloromethane (0.2 mL) wasadded 0.14 mmol of HCl (1M in Et₂O), the solvent evaporated under vacuoand the material thus obtained triturated with Et₂O to give 69 mg of thetitle compound as a white slightly hygroscopic solid (59% yield).

[The procedure may in analogy be adapted to other combinations of1-substituted 3-azabicyclo[3.1.0]hexanes and 3-substituted5-[(3-chloropropyl)thio]-4-methyl-4H-1,2,4-triazols. An equivalent molaramount of K₂CO₃ may be used to replace Na₂CO₃.]

NMR (¹H, DMSO): δ 10.57 (bs, 1H), 8.28 (bs, 1H), 8.2 (d, 1H), 7.94 (t,1H), 7.82 (d, 1H), 7.56 (d, 1H), 7.25 (d, 2H), 6.91 (d, 2H), 4.01 (dd,1H), 3.7 (m, 1H), 3.74 (s, 3H), 3.6-3.2 (m, 6H), 3.42 (s, 3H), 2.75 (s,3H), 2.24 (quint, 2H), 2.08 (quint, 1H), 1.62/1.05 (t/t, 2H). MS (m/z):486.3 [MH]⁺.

Example 1 was separated to give the separated enantiomers bysemipreparative Supercritical Fluid Chromatography (Gilson) using achiral column Chiralpak AD-H, 25×2.1 cm, eluent CO₂ containing 20%(ethanol+0.1% isopropanol), flow rate 25 mL/min, P 194 bar, T 35° C.,detection UV at 220 nm, loop 1 mL. Retention times given were obtainedusing an analytical Supercritical Fluid Chromatography (Gilson) using achiral column Chiralpak AD-H, 25×0.46 cm, eluent CO₂ containing 20%(ethanol+0.1% isopropanol), flow rate 2.5 mL/min, P 194 bar, T 35° C.,detection UV at 220 nm.

Enantiomer 1 was recovered in 15 mg yield as white solid (y=27%) fromthe racemate (60 mg). Rt.=39.2 min.

Enantiomer 2 was recovered in 17 mg yield as white solid (y=30%) fromthe racemate (60 mg). Rt.=43.4 min.

Enantiomer 1 showed fpKi (D3)>1 log-unit higher than Enantiomer 2.

Example 25-[5-({3-[(1R,5S/1S,5R)-1-(4-Bromophenyl)-3-azabicyclo[3.1.0]hex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazol-3-yl]-2-methylquinolinehydrochloride

The title compound was prepared in analogy to the method described inExample 1 in 39 mg yield as a white slightly hygroscopic solid (y=40%)from (1R,5S/1S,5R)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]hexane (40 mg).

NMR (¹H, DMSO): δ 10.28 (bs, 1H), 8.16 (dd, 2H), 7.89 (dd, 1H), 7.76 (d,1H), 7.55 (d, 2H), 7.49 (d, 1H), 7.28 (d, 2H), 4.06 (bm, 1H), 3.77 (bm,1H), 3.6 (bm, 2H), 3.44 (s, 3H), 3.5-3.2 (bm, 4H), 2.71 (s, 3H), 2.23(m, 3H), 1.58/1.14 (t/m, 2H). MS (m/z): 534.1 [MH]⁺, 1 Br.

Example 2 was separated to give the separated enantiomers bysemipreparative Supercritical Fluid Chromatography (Gilson) using achiral column Chiralcel OJ-H, 25×2.1 cm, eluent CO₂ containing 12%(ethanol+0.1% isopropylamine), flow rate 2.5 mL/min, P 196 bar, T 36°C., detection UV at 220 nm, loop 1 mL. Retention times given wereobtained using an analytical Supercritical Fluid Chromatography (Gilson)using a chiral column Chiralcel OJ-H, 25×0.46 cm, eluent CO₂ containing10% (ethanol+0.1% isopropylamine), flow rate 2.5 mL/min, P 196 bar, T35° C., detection UV at 220 nm.

Enantiomer 1 was recovered in 7 mg yield as white solid, hydrochloridesalt from the racemate (39 mg). Rt.=56.8 min. Purity >99% a/a by UV.

Enantiomer 2 was recovered in 7 mg yield as white solid, hydrochloridesalt from the racemate (39 mg). Rt.=62.5 min. Purity >99% a/a by UV.

The absolute configuration of Enantiomer 1 was assigned usingcomparative VCD and comparative OR analyses of the corresponding freebase to be5-[5-({3-[(1R,5S)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]hex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazol-3-yl]-2-methylquinoline.(1S,5R)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane (seePreparation 48) was used as the reference.

The absolute configuration of Enantiomer 2 was assigned as described forEnantiomer 1 to be5-[5-({3-[(1S,5R)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]hex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazol-3-yl]-2-methylquinoline.

Enantiomer 1: Specific Optical Rotation of the corresponding free base:[α]_(D)=+47° (CHCl₃, T=20° C., c=0.066 g/mL).

Enantiomer 2: Specific Optical Rotation of the corresponding free base:[α]_(D)=−42° (CHCl₃, T=20° C., c=0.065 g/mL).

Enantiomer 2 showed fpKi (D3)>1 log-unit higher than Enantiomer 1.

Example 32-Methyl-5-[4-methyl-5-({3-[(1R,5S/1S,5R)-1-phenyl-3-azabicyclo[3.1.0]hex-3-yl]propyl}thio)-4H-1,2,4-triazol-3-yl]quinolinehydrochloride

The title compound was prepared in analogy to the method described inExample 1 in 74 mg yield as a white slightly hygroscopic solid (y=59%)from (1R,5S/1S,5R)-1-phenyl-3-azabicyclo[3.1.0]hexane (40 mg).

NMR (¹H, DMSO): δ 10.4 (bs, 1H), 8.3 (bs, 1H), 8.2 (d, 1H), 7.9 (t, 1H),7.8 (d, 1H), 7.6 (bd, 1H), 7.4-7.3 (m, 5H), 4.0-3.5 (m/m, 2H), 3.7-3.45(m/m, 2H), 3.5-3.3 (m, 7H), 2.73 (s, 3H), 2.3 (m, 3H), 1.60, 1.1 (t, t2H). MS (m/z): 456.3 [MH]⁺.

Example 3 was separated to give the separated enantiomers bysemi-preparative HPLC using a chiral column Chiralcel OD 10 μm, 250×20mm, eluent A: n-hexane; B: isopropanol, gradient isocratic 35% B, flowrate 7 mL/min, detection UV at 200-400 nm, CD 230 nm. Retention timesgiven were obtained using an analytical HPLC using a chiral columnChiralcel OD 5 μm, 250×4.6 mm, eluent A: n-hexane; B: isopropanol,gradient isocratic 25% B, flow rate 1 mL/min, detection UV at 200-400nm.

Enantiomer 1 was recovered in 15 mg yield as white solid (y=27%) fromthe racemate (60 mg). Rt.=39.2 min.

Enantiomer 2 was recovered in 17 mg yield as white solid (y=30%) fromthe racemate (60 mg). Rt.=43.4 min.

Enantiomer 2 showed fpKi (D3)>1 log-unit higher than Enantiomer 1.

Example 45-[5-({3-[(1R,5S/1S,5R)-1-(3,4-Dichlorophenyl)-3-azabicyclo[3.1.0]hex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazol-3-yl]-2-methylquinolinehydrochloride

The title compound was prepared in analogy to the method described inExample 1 in 65 mg yield as a white slightly hygroscopic solid (y=52%)from (1R,5S/1S,5R)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane (50mg).

NMR (¹H, DMSO): δ 10.6 (s, 1H), 8.32 (bs, 1H), 8.21 (d, 1H), 7.96 (d,1H), 7.84 (d, 1H), 7.66 (d, 1H), 7.61 (d, 1H), 7.6 (d, 1H), 7.31 (dd,1H), 4.06 (m, 2H), 3.74 (m, 2H), 3.7-3.2 (m, 4H), 3.36 (s, 3H), 2.76 (s,3H), 2.25 (m, 4H), 1.69 (m, 1H), 1.2 (m, 1H). MS (m/z): 524.3 [MH]⁺,2Cl.

Example 4 was separated to give the separated enantiomers bysemipreparative Supercritical Fluid Chromatography (Gilson) as describedin Example 1.

Enantiomer 1 was recovered in 19 mg yield as white solid (y=36%) fromthe racemate (56 mg). Rt.=26.9 min.

The absolute configuration of Enantiomer 1 was assigned usingcomparative VCD and comparative OR analyses of the corresponding freebase to be5-[5-({3-[(1S,5R)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazol-3-yl]-2-methylquinoline.(1S,5R)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane (seePreparation 48) was used as the reference.

The absolute configuration of Enantiomer 2 was assigned as described forEnantiomer 1 to be5-[5-({3-[(1R,5S)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazol-3-yl]-2-methylquinoline.

Enantiomer 1: Specific Optical Rotation of the corresponding free base:[α]_(D)=−38.4° (CDCl₃, T=20° C., c=0.010 g/mL).

Enantiomer 2 was recovered in 14 mg yield as white solid (y=26%) fromthe racemate (56 mg). Rt.=31.4 min.

Enantiomer 2: Specific Optical Rotation of the corresponding free base:[α]_(D)=+34.4° (CDCl₃, T=20° C., c=0.010 g/mL).

Enantiomer 1 showed fpKi (D3)>0.6 log-unit higher than Enantiomer 2.

Example 55-[5-({3-[(1R,5S/1S,5R)-1-(4-tert-Butylphenyl)-3-azabicyclo[3.1.0]hex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazol-3-yl]-2-methylquinolinehydrochloride

The title compound was prepared in analogy to the method described inExample 1 in 38 mg yield as a white slightly hygroscopic solid (y=51%)from (1R,5S/1S,5R)-1-(4-tert-butylphenyl)-3-azabicyclo[3.1.0]hexane (29mg).

NMR (¹H, DMSO): δ 10.16 (bs, 1H), 8.15 (dd, 2H), 7.89 (t, 1H), 7.76 (d,1H), 7.49 (d, 1H), 7.36 (d, 2H), 7.23 (d, 2H), 4.05 (dd, 1H), 3.77 (dd,1H), 3.58 (m, 2H), 3.44 (s, 3H), 2.7 (bm, 4H), 2.34 (s, 3H), 2.23 (t,2H), 2.15 (t, 1H), 1.51 (t, 1H), 1.27 (s, 9H), 1.14 (m, 1H). MS (m/z):512.4 [MH]⁺.

Example 5 was separated to give the separated enantiomers bysemipreparative Supercritical Fluid Chromatography (Gilson) as describedin Example 1 but applying a pressure of 200 bar instead of 194 bar.

Enantiomer 1 was recovered in 6.5 mg yield as white solid (y=30%) fromthe racemate (23 mg). Rt.=7.0 min.

Enantiomer 2 was recovered in 5 mg yield as white solid (y=23%) from theracemate (23 mg). Rt.=7.8 min.

Enantiomer 2 showed fpKi (D3)>0.9 log-unit higher than Enantiomer 1.

Example 64-[(1R,5S/1S,5R)-3-(3-{[4-Methyl-5-(2-methylquinolin-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]benzonitrilehydrochloride

The title compound was prepared in analogy to the method described inExample 1 in 19 mg yield as a white slightly hygroscopic solid (y=27%)from (1R,5S/1S,5R)-1-(4-cyanophenyl)-3-azabicyclo[3.1.0]hexane (25 mg).

NMR (¹H, DMSO): δ 10.45 (bs, 1H), 8.26 (bd, 1H), 8.17 (d, 1H), 7.93 (t,1H), 7.8 (d/d, 3H), 7.5 (d, 1H), 7.46 (d, 2H), 4.09 (d, 1H), 3.76 (d,1H), 3.67 (t, 1H), 3.6-3.2 (bm, 5H), 3.43 (s, 3H), 2.73 (s, 3H), 2.34(m, 1H), 2.25 (quint., 2H), 1.71/1.22 (dt, 2H).

Example 74-[(1R,5S/1S,5R)-3-(3-{[4-Methyl-5-(2-methylquinolin-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]phenolhydrochloride

The title compound was prepared in analogy to the method described inExample 1 in 10 mg yield as a white slightly hygroscopic solid (y=11%)from (1R,5S/1S,5R)-1-(4-hydroxyphenyl)-3-azabicyclo[3.1.0]hexane (38mg).

NMR (¹H, DMSO): δ 10.17 (bs, 1H), 9.4 (s, 1H), 8.15 (bd, 2H), 7.89 (d,1H), 7.75 (d, 1H), 7.48 (d, 1H), 7.12 (d, 2H), 6.73 (d, 2H), 3.98 (dd,1H), 3.74 (m, 1H), 3.5 (bm, 2H), 3.44 (s, 3H), 3.5-3.2 (bm, 4H), 2.7 (s,3H), 2.22 (bquint. 2H), 2.03 (m, 1H), 1.46/1.03 (dm, 2H). MS (m/z):486.2 [MH]⁺.

Example 8(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-phenyl-3-azabicyclo[3.1.0]hexanehydrochloride

The title compound was prepared in analogy to the method described inExample 1 in 75 mg yield as a white slightly hygroscopic solid (y=70%)from (1R,5S/1S,5R)-1-phenyl-3-azabicyclo[3.1.0]hexane (40 mg).

NMR (¹H, DMSO): δ 10.46 (bs, 1H), 8.58 (s, 1H), 7.4-7.2 (m, 5H), 4.04(dd, 1H), 3.73 (m, 1H), 3.7 (s, 3H), 3.7-3.4 (m, 2H), 3.4-3.2 (m+t, 4H),2.39 (s, 3H), 2.17 (m, 3H), 1.64, 1.1 (2t, 2H).

Example 9(1R,5S/1S,5R)-1-(4-Bromophenyl)-3-(3-({[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexanehydrochloride

The title compound was prepared in analogy to the method described inExample 1 in 24 mg yield as a white slightly hygroscopic solid (y=28%)from (1R,5S/1S,5R)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]hexane (40 mg).

NMR (¹H, DMSO): δ 10.29 (bs, 1H), 8.58 (s, 1H), 7.55 (dd, 2H), 7.27 (dd,2H), 4.03 (dd, 1H), 3.73 (dd, 1H), 3.7 (s, 3H), 3.55 (m, 2H),3.5-3.2/3.28 (m+t, 4H), 2.39 (s, 3H), 2.19 (m, 3H), 1.59/1.12 (2t, 2H).MS (m/z): 474.1 [MH]⁺.

Example 9 was separated to give the separated enantiomers bysemipreparative Supercritical Fluid Chromatography (Gilson) using achiral column Chiralcel AS-H, 25×2.1 cm, eluent CO₂ containing 11%(ethanol+0.1% isopropylamine), flow rate 22 mL/min, P 192 bar, T 36° C.,detection UV at 220 nm, loop 2 mL. Retention times given were obtainedusing an analytical Supercritical Fluid Chromatography (Gilson) using achiral column Chiralpak AS-H, 25×0.46 cm, eluent CO₂ containing 10%(ethanol+0.1% isopropyilamine), flow rate 2.5 mL/min, P 199 bar, T 35°C., detection UV at 220 nm.

Enantiomer 1 was recovered in 59 mg yield as white solid, hydrochloridesalt from the racemate (138 mg). Rt.=22.2 min. Purity >99% a/a by UV

Enantiomer 2 was recovered in 50 mg yield as white solid, hydrochloridesalt from the racemate (138 mg). Rt.=30.8 min. Purity >99% a/a by UV

The absolute configuration of Enantiomer 1 was assigned usingcomparative VCD and comparative OR analyses of the corresponding freebase to be(1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane.(1R,5S)-1-(4-Bromophenyl)-3-azabicyclo[3.1.0]hexane (compare Preparation32) was used as the reference.

The absolute configuration of Enantiomer 2 was assigned as described forEnantiomer 1 to be(1R,5S)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane.

Enantiomer 1: Specific Optical Rotation of the corresponding free base:[α]_(D)=−51° (CHCl₃, T=20° C., c=0.00913 g/mL).

Enantiomer 2: Specific Optical Rotation of the corresponding free base:[α]_(D)=+27° (CHCl₃, T=20° C., c=0.0113 g/mL).

Enantiomer 1 showed fpKi (D3)>1 log-unit higher than Enantiomer 2.

Example 10(1R,5S/1S,5R)-1-(4-tert-Butylphenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexanehydrochloride

The title compound was prepared in analogy to the method described inExample 1 in 52 mg yield as a white slightly hygroscopic solid (y=57%)from (1R,5S/1S,5R)-1-(4-tert-butylphenyl)-3-azabicyclo[3.1.0]hexane (40mg).

NMR (¹H, CD3OD): δ 8.4 (s, 1H), 7.42 (d, 2H), 7.28 (d, 2H), 4.11 (d,1H), 3.88 (d, 1H), 3.8 (s, 3H), 3.65 (m, 2H), 3.43 (t, 2H), 3.39 (t,2H), 2.47 (s, 3H), 2.29 (m, 2H), 2.21 (m, 1H), 1.44 (m, 1H), 1.33 (s,9H), 1.3 (m, 1H). MS (m/z): 452.3 [MH]⁺.

Example 11(1R,5S/1S,5R)-1-(3,4-Dichlorophenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexanehydrochloride

The title compound was prepared in analogy to the method described inExample 1 in 35 mg yield as a white slightly hygroscopic solid (y=32%)from (1R,5S/1S,5R)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane (50mg).

NMR (¹H, DMSO): δ 10.11 (vbs, 1H), 8.58 (s, 1H), 7.6 (d+d, 2H), 6.29(dd, 1H), 4.04/3.74 (2dd, 2H), 3.7 (s, 3H), 3.6-3.2 (m, 4H), 3.28 (t,2H), 2.39 (s, 3H), 2.26 (quint, 1H), 2.15 (quint., 2H), 1.53/1.2 (2t,2H). MS (m/z): 464.1 [MH]⁺, 2Cl.

Example 11 was separated to give the separated enantiomers bysemipreparative Supercritical Fluid Chromatography (Gilson) using achiral column Chiralpak AS-H, 25×2.1 cm, eluent CO₂ containing 8%(ethanol+0.1% isopropylamine), flow rate 22 mL/min, P 194 bar, T 36° C.,detection UV at 220 nm, loop 1 mL. Retention times given were obtainedusing an analytical Supercritical Fluid Chromatography (Gilson) using achiral column Chiralpak AS-H, 25×0.46 cm, eluent CO₂ containing 8%(ethanol+0.1% isopropylamine), flow rate 2.5 mL/min, P 190 bar, T 35°C., detection UV at 220 nm.

Enantiomer 1 was recovered in 12.5 mg yield as white solid,hydrochloride salt from the racemate (29 mg). Rt.=38.0 min. Purity 98.6%a/a by UV.

Enantiomer 2 was recovered in 12.5 mg yield as white solid,hydrochloride salt from the racemate (29 mg). Rt.=40.8 min. Purity 98.6%a/a by UV.

Enantiomer 1 showed fpKi (D3)>0.5 log-units higher than Enantiomer 2.

Example 12(1R,5S/1S,5R)-1-(4-methoxyphenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexanehydrochloride

The title compound was prepared in analogy to the method described inExample 1 in 38 mg yield as a white slightly hygroscopic solid (y=39%)from (1R,5S/1S,5R)-1-(4-methoxyphenyl)-3-azabicyclo[3.1.0]hexane (40mg).

NMR (¹H, DMSO): δ 10.18 (bs, 1H), 8.58 (s, 1H), 7.24 (d, 2H), 6.91 (d,2H), 3.97 (dd, 1H), 3.74 (s, 3H), 3.7 (s, 3H), 3.7 (m, 1H), 3.6-3.2 (m,4H), 3.27 (t, 2H), 2.39 (s, 3H), 2.15 (quint, 2H), 2.07 (quint., 1H),1.49/1.05 (2t, 2H). MS (m/z): 426.2 [MH]⁺.

Example 12 was separated to give the separated enantiomers bysemipreparative Supercritical Fluid Chromatography (Gilson) using achiral column Chiralpak AS-H, 25×2.1 cm, eluent CO₂ containing 9%(ethanol+0.1% isopropylamine), flow rate 22 mL/min, P 192 bar, T 36° C.,detection UV at 220 nm, loop 1 mL. Retention times given were obtainedusing an analytical Supercritical Fluid Chromatography (Gilson) using achiral column Chiralpak AS-H, 25×0.46 cm, eluent CO₂ containing 8%(ethanol+0.1% isopropylamine), flow rate 2.5 mL/min, P 190 bar, T 35°C., detection UV at 220 nm.

Enantiomer 1 was recovered in 5 mg yield as white solid, hydrochloridesalt from the racemate (30 mg). Rt.=28.7 min. Purity >99% a/a by UV.

Enantiomer 2 was recovered in 12.5 mg yield as white solid,hydrochloride salt from the racemate (30 mg). Rt.=36.4 min. Purity >99%a/a by UV.

Enantiomer 1 showed fpKi (D3)>1 log-unit higher than Enantiomer 2.

Example 13(1R,5S/1S,5R)-1-[4-(5-methyl-3-isoxazolyl)phenyl]-3-(3-({[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexanehydrochloride

The title compound was prepared in analogy to the method described inExample 1 in 30 mg yield as a white slightly hygroscopic solid (y=25%)from(1R,5S/1S,5R)-1-[4-(5-methyl-3-isoxazolyl)phenyl]-3-azabicyclo[3.1.0]hexane(55 mg).

NMR (¹H, CD₃OD): δ 8.37 (s, 1H), 7.8 (d, 2H), 7.43 (d, 2H), 6.55 (s,1H), 4.16/3.88 (2d, 2H), 3.78 (s, 3H), 3.7 (m, 2H), 3.48-3.4 (2t, 4H),2.48 (s, 3H), 2.45 (s, 3H), 2.29 (m, 3H), 1.51/1.37 (2t, 2H). MS (m/z):477.2 [MH]⁺.

Example 14(1S,5R)-3-(3-{[4-Methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane

A mixture of(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane(Preparation 18, 10.4 g),3-[(3-chloropropyl)thio]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole(Preparation 14, 15.0 g), K₂CO₃ (7.5 g) and NaI (8.23 g) in DMF(anhydrous, 100 mL) were heated at 60° C. for 15 h. The mixture was thenallowed to cool to room temperature, diluted with Et₂O (250 mL) andwater (200 mL). After separation of the two phases, the aqueous layerwas extracted again with Et₂O (2×200 mL). The combined organic layerswere washed with water (2×150 mL) and then dried over Na₂SO₄. Afterevaporation of the solvent in vacuo, the crude product was purified byflash chromatography (dichloromethane to 10% MeOH in dichloromethane) togive 16.5 g of a yellow solid. The material thus obtained was trituratedwith Et₂O to provide the title compound (13 g) as white solid (y=61%).

Assignment of the configuration of the title compound is based on twolines of evidence: The fact that it was prepared from(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (ofknown configuration, see Preparation 14) and by comparison with thespectroscopic data obtained for(1S,5R)-1-[4-(trifluoromethyl)-phenyl]-3-azabicyclo[3.1.0]hexane: Bandsin the VCD spectrum of the title compound are coincident with thecorresponding bands in the spectrum of(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane,additionally the sign of the specific rotation is the same for bothcompounds.

NMR (¹H, CDCl₃): δ 7.89 (m, 1H), 7.49 (d, 2H), 7.18 (d, 2H), 3.67 (s,3H), 3.31 (m, 2H), 3.30 (d, 1H), 3.09 (d, 1H), 2.61 (m, 2H), 2.56 (d,1H), 2.5 (s, 3H), 2.45 (d, 1H), 1.97 (m, 2H), 1.73 (m, 1H), 1.47 (t,1H), 0.8 (dd, 1H). MS (m/z): 464 [MH]⁺.

Example 15(1S,5R)-3-(3-{[4-Methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexanehydrochloride

Hydrochloric acid (1M solution in Et₂O, 19.4 mL) was added dropwiseunder N₂ to a solution of(1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane(Example 14, 9 g) in Et₂O (anhydrous, 135 mL). The resulting suspensionwas allowed to stir at room temperature for 2 h. The solid was thenfiltered, washed with Et₂O and dried in vacuo overnight to provide thetitle compound (8.9 g) as off white solid (y=92%).

NMR (¹H, DMSO): δ 10.16 (bs, 1H), 8.58 (s, 1H), 7.72 (d, 2H), 7.51 (d,2H), 4.1 (dd, 1H), 3.78 (dd, 1H), 3.70 (s, 3H), 3.66 (m, 2H), 3.29 (t,2H), 2.5 (bm, 2H), 2.39 (s, 3H), 2.33 (quint, 2H), 2.19 (m, 1H),1.62/1.23 (t/t, 2H). MS (m/z): 464 [MH]⁺.

Example 16(1R,5S/1S,5R)-1-[2-Fluoro-4-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]-hexanehydrochloride

A mixture of(1R,5S/1S,5R)-1-[2-Fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo-[3.1.0]hexane(Preparation 38, 700 mg, 2.8 mmol),3-[(3-Chloropropyl)thio]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole(Preparation 14, 3.4 mmol), Na₂CO₃ (3.4 mmol) and NaI (3.4 mmol) in DMF(anhydrous, 6 mL) was heated at 60° C. for 24 h. After elimination ofthe solvent under vacuo, the residue was dissolved in ethyl acetate andthe organic layer was washed with saturated aqueous NaHCO₃ and driedover Na₂SO₄. This solution was filtered and the filtrate wasconcentrated in vacuo. The crude was purified by flash chromatography(dichloromethane to 10% MeOH in dichloromethane) to give 503 mg of thefree base of the title compound.

NMR (¹H, CDCl₃): δ 7.89 (s, 1H), 7.32-7.2 (m, 3H), 3.70 (s, 3H), 3.30(t, 2H), 3.26 (dd, 1H), 3.10 (dd, 1H), 2.60 (t, 2H), 2.52 (dd, 1H), 2.51(s, 3H), 2.43 (dd, 1H), 1.94 (m, 2H), 1.74 (m, 1H), 1.40 (t, 1H), 0.76(dd, 1H). MS (m/z): 482.2 [MH]⁺.

The title compound was obtained as a white solid following the methoddescribed for Example 15.

NMR (¹H, DMSO): δ 10.28 (bs, 1H), 8.58 (s, 1H), 7.73 (d, 1H), 7.6 (m,2H), 4/3.57 (d/m, 2H), 3.79 (d, 1H), 3.69 (s, 3H), 3.5-3.2 (vbm, 1H),3.27 (t, 2H), 2.5 (m, 2H), 2.4 (m, 1H), 2.38 (s, 3H), 2.14 (quint., 2H),1.62/1.16 (2t, 2H). MS (m/z): 481 [MH]⁺.

Example 16 was separated to give the separated enantiomers bysemi-preparative HPLC using a chiral column Chiralpak AD 10 μm, 250×21mm, eluent A: n-hexane; B: isopropanol+0.1% isopropyl amine, gradientisocratic 9% B, flow rate 7 mL/min, detection UV at 200-400 nm.Retention times given were obtained using an analytical HPLC using achiral column Chiralpak AD-H 5 μm, 250×4.6 mm, eluent A: n-hexane; B:isopropanol, gradient isocratic 15% B, flow rate 0.8 mL/min, detectionUV at 200-400 nm. Enantiomer 1 was recovered as white solid, Rt.=15.4min.

Enantiomer 2 was recovered as white solid, Rt.=16.3 min.

Enantiomer 2 showed fpKi (D3)>1 log-unit higher than Enantiomer 1.

Example 17(1R,5S/1S,5R)-3-(3-{[4-Methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[3-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexanehydrochloride

(1R,5S/1S,5R)-1-[3-(Trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexanewas prepared in analogy to the method described in Preparations 15, 16and 17. From this material the title compound was obtained as a whiteslightly hygroscopic solid following the method described for Examples14 and 15.

NMR (¹H, DMSO): δ 10.5 (bs, 1H), 8.58 (s, 1H), 7.7-7.5 (m, 4H), 4.09 (m,1H), 3.8-3.2 (m, 8H), 3.29 (t, 2H), 2.39 (s, 3H), 2.3 (m, 1H), 2.18 (m,2H), 1.68 (t, 1H), 1.21 (t, 1H). MS (m/z): 464 [MH]⁺.

Example 17 was separated to give the separated enantiomers bysemipreparative Supercritical Fluid Chromatography (Gilson) using achiral column Chiralpak AD-H, 25×0.46 cm, eluent CO₂ containing 10%(ethanol+0.1% isopropanol), flow rate 2.5 mL/min, P 180 bar, T 35° C.,detection UV at 220 nm, loop 1 mL. Retention times given were obtainedusing an analytical Supercritical Fluid Chromatography (Gilson) using achiral column Chiralpak AD-H, 25×0.46 cm, eluent CO₂ containing 10%(ethanol+0.1% isopropanol), flow rate 22 mL/min, P 190 bar, T 36° C.,detection UV at 220 nm.

Enantiomer 1 was recovered as white solid, Rt.=17.6 min.

Enantiomer 2 was recovered as white solid, Rt.=18.4 min.

Enantiomer 1 showed fpKi (D3)>1 log-unit higher than Enantiomer 2.

Example 18(1R,5S/1S,5R)-1-[4-Fluoro-3-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]-hexanehydrochloride

(1R,5S/1S,5R)-1-[4-Fluoro-3-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexanewas prepared in analogy to the method described in Preparations 15, 16and 17. From this material the title compound was obtained as a whiteslightly hygroscopic solid following the method described for Examples14 and 15.

NMR (¹H, DMSO): δ 10.2 (bs, 1H), 8.58 (s, 1H), 7.75 (dm, 1H), 7.72 (m,1H), 7.53 (t, 1H), 4.06 (dd, 1H), 3.74 (dd, 1H), 3.7 (s, 3H), 3.6 (m,2H), 3.4 (m, 2H), 3.28 (t, 2H), 2.39 (s, 3H), 2.26 (m, 1H), 2.18 (m,2H), 1.54 (t, 1H), 1.22 (dd, 1H). MS (m/z): 481 [MH]⁺.

Example 191-[5-[(1S,5R/1R,5S)-3-(3-{[4-Methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]-2-(methyloxy)phenyl]ethanonehydrochloride

The title compound was prepared in analogy to the method described inExample 1 in 25 mg yield as a white slightly hygroscopic solid from(1R,5S/1S,5R)-1-[5-(3-azabicyclo[3.1.0]hex-1-yl)-2-(methyloxy)phenyl]ethanone(32 mg).

NMR (¹H, DMSO): δ 10.31 (bs, 1H), 8.58 (s, 1H), 7.52 (d, 1H), 7.49 (dd,1H), 7.16 (d, 1H), 3.98 (dd, 1H), 3.89 (s, 3H), 3.7 (m, 4H), 3.6-3.2(bm, 4H), 3.27 (t, 2H), 2.5 (m, 3H), 2.39 (s, 3H), 2.15 (quint, 2H),2.09 (quint, 1H), 1.54-1.08 (2t, 2H). MS (m/z): 468 [MH]⁺.

Example 19 was separated to give the separated enantiomers bysemipreparative Supercritical Fluid Chromatography (Gilson) using achiral column Chiralpak AS-H, 25×2.1 cm, eluent CO₂ containing 15%(ethanol+0.1% isopropylamine), flow rate 22 mL/min, P 196 bar, T 36° C.,detection UV at 220 nm, loop 1 mL. Retention times given were obtainedusing an analytical Supercritical Fluid Chromatography (Gilson) using achiral column Chiralpak AS-H, 25×0.46 cm, eluent CO₂ containing 15%(ethanol+0.1% isopropylamine), flow rate 2.5 mL/min, P 190 bar, T 35°C., detection UV at 220 nm.

Enantiomer 1 was recovered in 14 mg yield as white solid, hydrochloridesalt from the racemate (40 mg). Rt.=12.5 min. Purity >99% a/a by UV

Enantiomer 2 was recovered in 16 mg yield as white solid, hydrochloridesalt from the racemate (40 mg). Rt.=16.8 min. Purity >99% a/a by UV

Enantiomer 1 showed fpKi (D3)>1 log-unit higher than Enantiomer 2.

Example 20(1S,5R/1R,5S)-1-(4-Chlorophenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexanehydrochloride

The title compound was prepared in analogy to the method described inExample 1 in 99 mg yield as a white slightly hygroscopic solid from(1R,5S/1S,5R)-1-(4-chlorophenyl)-3-azabicyclo[3.1.0]hexane (58 mg).

NMR (¹H, DMSO): δ 9.93 (bs, 1H), 8.58 (s, 1H), 7.42 (d, 2H), 7.33 (d,2H), 4.04 (dd, 1H), 3.75 (dd, 1H), 3.7 (s, 3H), 3.5 (m, 2H), 3.3 (bm,4H), 2.39 (s, 3H), 2.2 (m, 1H), 2.15 (m, 2H), 1.47-1.14 (2t, 2H). MS(m/z): 431 [MH]⁺.

Example 20 was separated to give the separated enantiomers bysemipreparative Supercritical Fluid Chromatography (Gilson) using achiral column Chiralpak AS-H, 25×2.1 cm, eluent CO₂ containing 15%(ethanol+0.1% isopropylamine), flow rate 22 mL/min, P 192 bar, T 36° C.,detection UV at 220 nm, loop 1 mL. Retention times given were obtainedusing an analytical Supercritical Fluid Chromatography (Gilson) using achiral column Chiralpak AS-H, 25×0.46 cm, eluent CO₂ containing 15%(ethanol+0.1% isopropylamine), flow rate 2.5 mL/min, P 190 bar, T 35°C., detection UV at 220 nm.

Enantiomer 1 was recovered in 17 mg yield as white solid, hydrochloridesalt from the racemate (40 mg). Rt.=7.8 min. Purity >99% a/a by UV

Enantiomer 2 was recovered in 17 mg yield as white solid, hydrochloridesalt from the racemate (40 mg). Rt.=9.7 min. Purity >99% a/a by UV

The absolute configuration of Enantiomer 1 was assigned usingcomparative VCD and comparative OR analyses of the corresponding freebase to be(1S,5R)-1-(4-chlorophenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane.5-[5-({3-[(1R,5S)-1-(4-Bromophenyl)-3-azabicyclo[3.1.0]hex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazol-3-yl]-2-methylquinoline(compare Example 2) was used as the reference.

The absolute configuration of Enantiomer 2 was assigned as described forEnantiomer 1 to be(1R,5S)-1-(4-chlorophenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane.

Enantiomer 1: Specific Optical Rotation of the corresponding free base:[α]_(D)=−25° (CHCl₃, T=20° C., c=0.0066 g/mL).

Enantiomer 2: Specific Optical Rotation of the corresponding free base:[α]_(D)=+ 29° (CHCl₃, T=20° C., c=0.0068 g/mL).

Enantiomer 1 showed fpKi (D3)>1 log-unit higher than Enantiomer 2.

Example 21(1S,5R/1R,5S)-1-(4-Fluorophenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexanehydrochloride

The title compound was prepared in analogy to the method described inExample 1 in 78 mg yield as a white slightly hygroscopic solid from(1R,5S/1S,5R)-1-(4-florophenyl)-3-azabicyclo[3.1.0]hexane (49 mg).

NMR (¹H, DMSO): δ 10.06 (bs, 1H), 8.58 (s, 1H), 7.36 (dd, 2H), 7.19 (t,2H), 4.02 (dd, 1H), 3.74 (dd, 1H), 3.7 (s, 3H), 3.55 (m, 2H), 3.5-3.2(bm, 4H), 2.39 (s, 3H), 2.15 (m, 3H), 1.49-1.1 (2t, 2H). MS (m/z): 414[MH]⁺.

Example 21 was separated to give the separated enantiomers bysemipreparative Supercritical Fluid Chromatography (Gilson) using achiral column Chiralpak AS-H, 25×2.1 cm, eluent CO₂ containing 7%(ethanol+0.1% isopropylamine), flow rate 22 mL/min, P 196 bar, T 36° C.,detection UV at 220 nm, loop 1 mL. Retention times given were obtainedusing an analytical Supercritical Fluid Chromatography (Gilson) using achiral column Chiralpak AS-H, 25×0.46 cm, eluent CO₂ containing 6%(ethanol+0.1% isopropylamine), flow rate 2.5 mL/min, P 190 bar, T 35°C., detection UV at 220 nm.

Enantiomer 1 was recovered in 14 mg yield as white solid, hydrochloridesalt from the racemate (40 mg). Rt.=26.2 min. Purity >99% a/a by UV

Enantiomer 2 was recovered in 16 mg yield as white solid, hydrochloridesalt from the racemate (40 mg). Rt.=32.4 min. Purity >99% a/a by UV

Enantiomer 1 showed fpKi (D3)>1 log-unit higher than Enantiomer 2.

Example 22(1S,5R/1R,5S)-1-(3-Chlorophenyl)-5-methyl-3-(3-({[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexanehydrochloride

The title compound was prepared in analogy to the method described inExample 1 in 184 mg yield as a white slightly hygroscopic solid from(1R,5S/1S,5R)-1-(3-chlorophenyl)-3-azabicyclo[3.1.0]hexane (116 mg).

NMR (¹H, DMSO): δ 9.88 (bs, 1H), 8.58 (s, 1H), 7.43 (d, 1H), 7.4-7.2 (m,3H), 4.06 (dd, 1H), 3.75 (dd, 1H), 3.7 (s, 3H), 3.62-3.54 (t/m, 2H),3.5-3.3 (bm, 4H), 2.39 (s, 3H), 2.25 (m, 1H), 2.15 (m, 2H), 1.46-1.19(2m, 2H). MS (m/z): 431 [MH]⁺.

Example 22 was separated to give the separated enantiomers bysemipreparative Supercritical Fluid Chromatography (Gilson) using achiral column Chiralpak AD-H, 25×0.46 cm, eluent CO₂ containing 15%(ethanol+0.1% isopropylamine), flow rate 22 mL/min, P 192 bar, T 36° C.,detection UV at 220 nm, loop 1 mL. Retention times given were obtainedusing an analytical Supercritical Fluid Chromatography (Berger) using achiral column Chiralpak AD-H, 25×0.46 cm, eluent CO₂ containing 15%(ethanol+0.1% isopropylamine), flow rate 2.5 mL/min, P 180 bar, T 35°C., detection UV at 220 nm.

Enantiomer 1 was recovered in 18 mg yield as white solid, hydrochloridesalt from the racemate (40 mg). Rt.=29.6 min. Purity 100% a/a by UV.

Enantiomer 2 was recovered in 16 mg yield as white solid, hydrochloridesalt from the racemate (40 mg). Rt.=32.0 min. Purity 100% a/a by UV

Enantiomer 1 showed fpKi (D3)>1 log-unit higher than Enantiomer 2.

Example 23(1S,5R/1R,5S)-1-(3-Fluorophenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexanehydrochloride

The title compound was prepared in analogy to the method described inExample 1 in 150 mg yield as a white slightly hygroscopic solid from(1R,5S/1S,5R)-1-(3-fluorophenyl)-3-azabicyclo[3.1.0]hexane (116 mg).

NMR (¹H, DMSO): δ 10.21 (bs, 1H), 8.58 (d, 1H), 7.4 (m, 1H), 7.2-7.0 (m,3H), 4.03 (dd, 1H), 3.75 (dd, 1H), 3.7 (s, 3H), 3.61 (t/m, 1H), 3.52 (m,1H), 3.3 (m, 2H), 3.28 (t, 2H), 2.38 (s, 3H), 2.25 (m, 1H), 2.16 (m,2H), 1.57-1.17 (t/m, 2H). MS (m/z): 414 [MH]⁺.

Example 23 was separated to give the separated enantiomers bysemipreparative Supercritical Fluid Chromatography (Gilson) using achiral column Chiralpak AS-H, 25×2.1 cm, eluent CO₂ containing 7%(ethanol+0.1% isopropylamine), flow rate 22 mL/min, P 192 bar, T 36° C.,detection UV at 220 nm, loop 1 mL. Retention times given were obtainedusing an analytical Supercritical Fluid Chromatography (Gilson) using achiral column Chiralpak AS-H, 25×0.46 cm, eluent CO₂ containing 6%(ethanol+0.1% isopropylamine), flow rate 2.5 mL/min, P 190 bar, T 35°C., detection UV at 220 nm.

Enantiomer 1 was recovered in 12 mg yield as white solid, hydrochloridesalt from the racemate (40 mg). Rt.=24.6 min. Purity >99% a/a by UV

Enantiomer 2 was recovered in 14.5 mg yield as white solid,hydrochloride salt from the racemate (40 mg). Rt.=26.0 min. Purity >99%a/a by UV

Enantiomer 1 showed fpKi (D3)>1 log-unit higher than Enantiomer 2.

Example 24(1S,5R/1R,5S)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[3-(methyloxy)phenyl]-3-azabicyclo[3.1.0]hexanehydrochloride

The title compound was prepared in analogy to the method described inExample 1 in 140 mg yield as a white slightly hygroscopic solid from(1R,5S/1S,5R)-1-(3-methoxyphenyl)-3-azabicyclo[3.1.0]hexane (116 mg).

NMR (¹H, DMSO): δ 10.16 (bs, 1H), 8.58 (d, 1H), 7.26 (dd, 1H), 6.85 (m,3H), 4.03 (dd, 1H), 3.77 (s, 3H), 3.72 (dd, 1H), 3.7 (s, 3H), 3.6-3.3(bm, 4H), 3.28 (t/m, 2H), 2.39 (s, 3H), 2.18 (m, 3H), 1.53-1.1 (t/m,2H). MS (m/z): 426 [MH]⁺.

Example 24 was separated to give the separated enantiomers bysemipreparative Supercritical Fluid Chromatography (Gilson) using achiral column Chiralcel OJ-H, 25×2.1 cm, eluent CO₂ containing 13%(2-propanol+0.1% isopropylamine), flow rate 22 mL/min, P 200 bar, T 36°C., detection UV at 220 nm. Retention times given were obtained using ananalytical Supercritical Fluid Chromatography (Berger) using a chiralcolumn Chiralcel OJ-H, 25×0.46 cm, eluent CO₂ containing 13%(2-propanol+0.1% isopropylamine), flow rate 2.5 mL/min, P 180 bar, T 35°C., detection UV at 220 nm.

Enantiomer 1 was recovered in 13.5 mg yield as white solid,hydrochloride salt from the racemate (40 mg). Rt.=24.2 min. Purity >99%a/a by UV.

Enantiomer 2 was recovered in 13.5 mg yield as white solid,hydrochloride salt from the racemate (40 mg). Rt.=26.8 min. Purity >99%a/a by UV.

Enantiomer 1 showed fpKi (D3)>1 log-unit higher than Enantiomer 2.

Example 25(1S,5R)-1-(4-Bromophenyl)-3-(3-{[4-methyl-5-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexanehydrochloride

The title compound was prepared in analogy to the method described inExample 1 in 33 mg yield as a white slightly hygroscopic solid from(1S,5R)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]hexane (Preparation 32, 30mg).

NMR (¹H, CD3OD): δ 7.54 (d, 2H), 7.28 (d, 2H), 4.08 (m, 3H), 3.8-3.6 (m,2H), 3.72 (s, 3H), 3.65 (m, 3H), 3.47 (t, 2H), 3.3 (m, 3H), 2.25 (m,3H), 1.93 (m, 4H), 1.48-1.34 (2m, 2H). MS (m/z): 478 [MH]⁺.

Example 26(1S,5R)-1-(4-Bromophenyl)-3-[3-({4-methyl-5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}thio)propyl]-3-azabicyclo[3.1.0]hexanehydrochloride

The title compound was prepared in analogy to the method described inExample 1 in 36 mg yield as a white slightly hygroscopic solid from(1S,5R)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]hexane (Preparation 32, 30mg).

NMR (¹H, CD3OD): δ 7.96 (m, 4H), 7.54 (d, 2H), 7.29 (t, 2H), 4.14 (d,1H), 3.90 (m, 1H), 3.75 (s, 3H), 3.66 (m, 2H), 3.50 (m, 2H), 3.43 (t,2H), 2.30 (m, 3H), 1.50 (m, 1H), 1.34 (t, 1H). MS (m/z): 578 [MH]⁺.

Example 27(1S,5R)-1-(4-Bromophenyl)-3-(3-{[4-methyl-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexanehydrochloride

The title compound was prepared in analogy to the method described inExample 1 in 49 mg yield as a white slightly hygroscopic solid from(1S,5R)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]hexane (Preparation 32, 30mg).

NMR (¹H, CD3OD): δ 8.97 (m, 1H), 8.82 (m, 1H), 8.31 (m, 1H), 7.75 (m,1H), 7.53 (d, 2H), 7.29 (t, 2H), 4.15 (d, 1H), 3.90 (d, 1H), 3.75 (s,3H), 3.67 (m, 2H), 3.50 (m, 2H), 3.42 (t, 2H), 2.29 (m, 3H), 1.51 (m,1H), 1.34 (t, 1H). MS (m/z): 471 [MH]⁺.

Example 28(1S,5R)-1-(4-Bromophenyl)-3-(3-{[5-(3,4-difluorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexanehydrochloride

The title compound was prepared in analogy to the method described inExample 1 in 26 mg yield as a white slightly hygroscopic solid from(1S,5R)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]hexane (Preparation 32, 30mg).

NMR (¹H, CD3OD): δ 7.72 (m, 1H), 7.55 (m, 4H), 7.28 (d, 2H), 4.13 (d,1H), 3.89 (d, 1H), 3.7 (s, 3H), 3.64 (m, 2H), 3.43 (t, 2H), 3.38 (m,2H), 2.29 (m, 3H), 1.48 (m, 1H), 1.34 (t, 1H). MS (m/z): 506 [MH]⁺.

Example 296-[5-({3-[(1S,5R/1R,5S)-1-(4-Chlorophenyl)-3-azabicyclo[3.1.0]hex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazol-3-yl]-2-methylquinolinehydrochloride

The title compound was prepared in analogy to the method described inExample 1 in 110 mg yield as a white slightly hygroscopic solid from(1R,5S/1S,5R)-1-(4-chlorophenyl)-3-azabicyclo[3.1.0]hexane (87 mg).

NMR (¹H, CD3OD): δ 8.95 (d, 1H), 8.39 (d, 1H), 8.28 (t, 1H), 8.13 (d,1H), 7.96 (d, 1H), 7.37 (m, 4H), 4.17 (d, 1H), 3.93 (d, 1H), 3.71 (m,2H), 3.62 (s, 3H), 3.5 (2m, 4H), 3.04 (s, 3H), 2.37 (m, 2H), 2.27 (m,1H), 1.55 (m, 1H), 1.31 (m, 1H). MS (m/z): 490 [MH]⁺.

Example 29 was separated to give the separated enantiomers bysemipreparative Supercritical Fluid Chromatography (Gilson) using achiral column Chiralpak AD-H, 25×0.46 cm, eluent CO₂ containing 25%(ethanol+0.1% isopropylamine), flow rate 22 mL/min, P 199 bar, T 36° C.,detection UV at 220 nm. Retention times given were obtained using ananalytical Supercritical Fluid Chromatography (Berger) using a chiralcolumn Chiralpak AD-H, 25×0.46 cm, eluent CO₂ containing 25%(ethanol+0.1% isopropylamine), flow rate 2.5 mL/min, P 180 bar, T 35°C., detection UV at 220 nm.

Enantiomer 1 was recovered in 13.5 mg yield as white solid,hydrochloride salt from the racemate (40 mg). Rt.=24.3 min. Purity 87.6%a/a by UV.

Enantiomer 2 was recovered in 5 mg yield as white solid, hydrochloridesalt from the racemate (40 mg). Rt.=26.5 min. Purity 100% a/a by UV.

Enantiomer 1 showed fpKi (D3)>1 log-unit higher than Enantiomer 2.

Example 30(1S,5R/1R,5S)-3-(3-{[4-Methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-{4-[(trifluoromethyl)oxy]phenyl}-3-azabicyclo[3.1.0]hexanehydrochloride

The title compound was prepared in analogy to the method described inExample 1 in 246 mg yield as a white slightly hygroscopic solid from(1R,5S/1S,5R)-1-{4-[(trifluoromethyl)oxy]phenyl}-3-azabicyclo[3.1.0]hexane(205 mg).

NMR (¹H, DMSO): δ 10.33 (bs, 1H), 8.58 (s, 1H), 7.43 (d, 2H), 7.36 (d,2H), 4.04 (dd, 1H), 3.73 (dd, 1H), 3.7 (s, 3H), 3.6-3.2 (bm, 6H), 2.39(s, 3H), 2.2 (m, 3H), 1.61-1.16 (2t, 2H). MS (m/z): 480 [MH]⁺.

Example 30 was separated to give the separated enantiomers bysemi-preparative HPLC using a chiral column Chirapak AS-H, 25×2 cm,eluent A: n-hexane; B: isopropanol, gradient isocratic 15% B v/v, flowrate 7 mL/min, detection UV at 220 nm. Retention times given wereobtained using chiral column Chiracel OD, 25×0.46 cm, eluent A:n-hexane; B: isopropanol, gradient isocratic 10% B v/v, flow rate 1mL/min, detection UV at 220 nm.

Enantiomer 1 was recovered in 15 mg yield as white solid, hydrochloridesalt from the racemate (40 mg). Rt.=28.3 min. Purity >99% a/a by UV.

Enantiomer 2 was recovered in 16 mg yield as white solid, hydrochloridesalt from the racemate (40 mg). Rt.=50.6 min. Purity >99% a/a by UV.

Enantiomer 1 showed fpKi (D3)>1 log-unit higher than Enantiomer 2.

Example 31(1S,5R/1R,5S)-3-(3-{[4-Methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[2-methyl-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexanehydrochloride

The title compound was prepared in analogy to the method described inExample 1 in 46 mg yield as a white slightly hygroscopic solid from(1R,5S/1S,5R)-1-[2-methyl-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane(71.5 mg).

NMR (¹H, DMSO): δ 10.25 (bs, 1H), 8.58 (s, 1H), 7.6 (m, 3H), 3.97-3.7(dd/m, 2H), 3.79/3.4 (dd/m, 2H), 3.69 (s, 3H), 3.27 (t, 2H), 2.5 (m,2H), 2.48 (s, 3H), 2.38 (s, 3H), 2.2 (m, 1H), 2.13 (quint., 2H),1.61-1.01 (2t, 2H). MS (m/z): 478 [MH]⁺.

Example 32

not used

Example 33(1S,5R/1R,5S)-3-(3-{[4-Methyl-5-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-{4-[(trifluoromethyl)oxy]phenyl}-3-azabicyclo[3.1.0]hexanehydrochloride

The title compound was prepared in analogy to the method described inExample 1 in 72 mg yield as a white slightly hygroscopic solid from(1R,5S/1S,5R)-1-{4-[(trifluoromethyl)oxy]phenyl}-3-azabicyclo[3.1.0]hexane(100 mg).

NMR (¹H, DMSO): δ 10.45 (bs, 1H), 7.44 (d, 2H), 7.36 (d, 2H), 4.04 (bm,1H), 3.94 (dm, 2H), 3.73 (bm, 1H), 3.55 (s, 3H), 3.6-3.3 (bm, 6H), 3.22(t, 2H), 3.13 (m, 1H), 2.23 (m, 1H), 2.21 (m, 2H), 1.9-1.7 (m, 4H),1.63-1.16 (2t, 2H). MS (m/z): 483 [MH]⁺.

Example 33 was separated to give the separated enantiomers bysemipreparative Supercritical Fluid Chromatography (Gilson) using achiral column Chiralpak AS-H, 25×2.1 cm, eluent CO₂ containing 8%(2-propanol+0.1% isopropylamine), flow rate 22 mL/min, P 200 bar, T 36°C., detection UV at 220 nm. Retention times given were obtained using ananalytical Supercritical Fluid Chromatography (Berger) using a chiralcolumn Chiralpak AS-H, 25×0.46 cm, eluent CO₂ containing 8%(2-propanol+0.1% isopropylamine), flow rate 2.5 mL/min, P 180 bar, T 35°C., detection UV at 220 nm.

Enantiomer 1 was recovered in 15 mg yield as white solid, hydrochloridesalt from the racemate (65 mg). Rt.=23.2 min. Purity 100% a/a by UV.

Enantiomer 2 was recovered in 12 mg yield as white solid, hydrochloridesalt from the racemate (65 mg). Rt.=24.6 min. Purity 100% a/a by UV.

Enantiomer 1 showed fpKi (D3)>1 log-unit higher than Enantiomer 2.

Example 34(1R,5S/1S,5R)-1-(3-Bromophenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexanehydrochloride

The title compound was prepared in 23 mg yield as a white slightlyhygroscopic solid from(1R,5S/1S,5R)-1-(3-bromophenyl)-3-azabicyclo[3.1.0]hexane (140 mg) inanalogy to the method described in Example 1 and purifying the free baseof the title compound by preparative HPLC using a column X Terra MS C185 μm, 100×19 mm, eluent A: H₂O+0.1% TFA; B: CH₃CN+0.1% TFA, gradient 10%(B) for 1 min, from 10% (B) to 35% (B) in 12 min, flow rate 17 mL/min,detection UV at 200-400 nm. Retention times given were obtained usingcolumn X Terra MS C18 5 μm, 50×4.6 mm, eluent A: H₂O+0.1% TFA; B:CH₃CN+0.1% TFA, gradient isocratic 25% B v/v, flow rate 1 mL/min,detection UV at 200-400 nm. Rt.=6.26 min. Purity 96.4% a/a by UV.

NMR (1H, DMSO): δ 9.9 (bs, 1H), 8.58 (s, 1H), 7.57 (s, 1H), 7.47 (m,1H), 7.3 (m, 2H), 4.04 (m, 1H), 3.75 (dd, 1H), 3.7-3.2 (m, 6H), 3.7 (s,3H), 2.39 (s, 3H), 2.23 (m, 1H), 2.15 (m, 2H), 1.47 (t, 1H), 1.2 (t,1H). MS (m/z): 512 [MH]⁺.

Example 35(1S,5R)-3-(1-Methyl-3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexanehydrochloride

A mixture of(1S,5R)-3-(3-chloro-1-methylpropyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexanehexane (Preparation 20, 105 mg),4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione(0.43 mmol), TEA (0.46 mmol) and NaI (0.43 mmol) in DMF (anhydrous, 1.6mL) was heated at 60° C. for 12 h. After elimination of the solventunder vacuo, the residue was dissolved in ethyl acetate and the organiclayer was washed with H₂O and dried over Na₂SO₄. This solution wasconcentrated in vacuo, treated with cyclohexane and filtered to give 125mg of the free base of the title compound. To a solution of thismaterial in dichloromethane (0.2 mL) was added 0.34 mmol of HCl (1M inEt₂O), the solvent evaporated under vacuo and the material thus obtainedtriturated with Et₂O to give 105 mg of the title compound as a whiteslightly hygroscopic solid.

MS (m/z): 478 [MH]⁺.

Example 35 was separated to give the separated diastereoisomers bysemi-preparative HPLC using a chiral column Chirapak AD, 25×2 cm, eluentA: n-hexane; B: ethanol+0.1% isopropylamine, gradient isocratic 15% Bv/v, flow rate 7 mL/min, UV wavelength range 220-400 nm. Retention timesgiven were obtained using a chiral column Chiralpak AD-H, 25×0.46 cm,eluent A: n-hexane; B: ethanol+0.1% isopropylamine, gradient isocratic17% B v/v, flow rate 1 mL/min, UV wavelength range 200-400 nm.Diastereoisomer 1 was recovered in 30 mg yield as a white solid,hydrochloride salt from the diastereomeric mixture (105 mg). Rt.=17.9min. Purity 99.4% a/a by UV

NMR (¹H, DMSO): δ 10.33 (bs, 1H), 8.58 (s, 1H), 7.71 (d, 2H), 7.53 (d,2H), 4.07 (dd, 1H), 3.78 (dd, 1H), 3.7 (s, 3H), 3.7 (m, 1H), 3.56 (bs,2H), 3.4 (m, 1H), 3.18 (m, 1H), 2.4 (s, 3H), 2.4-2.3 (m, 1H), 2.26-2.09(m, 2H), 1.72 (m, 1H), 1.42 (d, 3H), 1.2 (m, 1H). MS (m/z): 478 [MH]⁺.

Diastereoisomer 2 was recovered in 46 mg yield as white solid,hydrochloride salt from the diastereomeric mixture (105 mg). Rt.=21.2min. Purity >99% a/a by UV

NMR (¹H, DMSO): δ 10.26 (bs, 1H), 8.58 (s, 1H), 7.7 (d, 2H), 7.51 (d,2H), 4.14 (dd, 1H), 3.8-3.6 (m, 3H), 3.7 (s, 3H), 3.53 (bs, 1H), 3.4 (m,1H), 3.18 (m, 1H), 2.38 (s, 3H), 2.4-2.25 (m, 2H), 2.1 (m, 1H), 1.69 (m,1H), 1.39 (d, 3H), 1.2 (m, 1H). MS (m/z): 478 [MH]⁺.

Example 36(1R,5S/1S,5R)-1-[2-Fluoro-5-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexanehydrochloride

The title compound was prepared in analogy to the method described inExample 1 in 144 mg yield as a white slightly hygroscopic solid from1(1R,5S/1S,5R)-[2-fluoro-5-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane(109 mg).

NMR (¹H, CD₃OD): δ 8.41 (s, 1H), 7.8 (m, 1H), 7.74 (m, 1H), 7.39 (t,1H), 4.13 (d, 1H), 3.95 (d, 1H), 3.81 (s, 3H), 3.73 (bd, 1H), 3.54 (d,1H), 3.48 (m, 2H), 3.41 (m, 2H), 2.48 (s, 3H), 2.39 (m, 1H), 2.28 (q,2H), 1.58 (m, 1H), 1.35 (m, 1H). MS (m/z): 482 [MH]⁺.

Example 36 was separated to give the separated enantiomers bysemi-preparative HPLC using a chiral column Chirapak AS-H, 25×2 cm,eluent A: n-hexane; B: isopropanol+0.1% isopropylamine, gradientisocratic 10% B v/v, flow rate 7 mL/min, detection UV at 220 nm.Retention times given were obtained using an analytical SupercriticalFluid Chromatography (Berger) using a chiral column Chiralpak AD-H,25×0.46 cm, eluent CO₂ containing 7% (ethanol+0.1% isopropylamine), flowrate 2.5 mL/min, P 180 bar, T 35° C., detection UV at 220 nm.

Enantiomer 1 was recovered in 48 mg yield as a white solid,hydrochloride salt from the racemate (138 mg). Rt.=21.2 min. Purity 100%a/a by UV

Enantiomer 2 was recovered in 46 mg yield as white solid, hydrochloridesalt from the racemate (138 mg). Rt.=22.7 min. Purity 99% a/a by UV

Enantiomer 2 showed fpKi (D3)>1 log-unit higher than Enantiomer 1.

Example 371-[4-[(1R,5S/1S,5R)-3-(3-{[4-Methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]-2-(methyloxy)phenyl]ethanonehydrochloride

The title compound was prepared in analogy to the method described inExample 1 in 70 mg yield as a white slightly hygroscopic solid from1-[4-[(1S,5R/1R,5S)-3-azabicyclo[3.1.0]hex-1-yl]-2-(methyloxy)phenyl]ethanone(87 mg).

NMR (¹H, CDCl₃) of the corresponding free base: δ 8.0 (s, 1H), 7.7 (d,1H), 6.7-6.8 (m, 2H), 3.9 (s, 3H), 3.7 (s, 3H), 3.35 (m, 4H), 3.1 (d,1H), 2.6 (m, 3H), 2.55 (s, 3H), 2.5 (s, 3H), 2.45 (m, 1H), 2.0 (m, 2H),1.75 (m, 1H), 0.8 (m, 1H). MS (m/z): 468 [MH]⁺.

Example 381-[4-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]-2-(methyloxy)phenyl]-1-propanonehydrochloride

The title compound was prepared in analogy to the method described inExample 1 in 75 mg yield as a white slightly hygroscopic solid from1-[(1S,5R/1R,5S)-3-azabicyclo[3.1.0]hex-1-yl)-2-(methyloxy)phenyl]-1-propanone(106 mg).

Free base NMR (¹H, CDCl₃): δ 7.9 (s, 1H), 6.65 (d, 1H), 6.7 (m, 2H), 3.9(s, 3H), 3.7 (s, 3H), 3.35 (m, 3H), 3.1 (d, 1H), 2.9 (m, 2H), 2.6 (m,3H), 2.5 (s, 3H), 2.45 (m, 1H), 2.0 (m, 2H), 1.8 (m, 1H), 1.1 (m, 3H),0.8 (m, 1H). MS (m/z): 482 [MH]⁺.

Example 39(1R,5S/1S,5R)-3-(3-{[4-Methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[2-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexanehydrochloride

The title compound was prepared in analogy to the method described inExample 1 in 7 mg yield as a white slightly hygroscopic solid from(1R,5S/1S,5R)-1-[2-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane(53 mg).

NMR (¹H, DMSO): δ 10.48 (bs, 1H), 8.55 (s, 1H), 7.9-7.6 (m, 4H), 3.9-3.1(bm, 8H), 3.68 (s, 3H), 2.36 (s, 3H), 2.13 (m, 2H), 1.66 (m, 1H), 1.2(m, 1H), 1.1 (m, 1H). MS (m/z): 464 [MH]⁺.

Example 40(1S,5R)-1-[2-Fluoro-4-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexanehydrochloride

The free base of the title compound was prepared in analogy to themethod described in Example 1 from(1S,5R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane.A mixture of(1S,5R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane(Preparation 39, 727 mg, 2.97 mmol),3-[(3-Chloropropyl)thio]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole(Preparation 14, 3.6 mmol.), K₂CO₃ (3.6 mmol.) and NaI (2.97 mmol) inDMF anhydrous was heated at 60° C. for 24 h. After elimination of thesolvent under vacuo, the residue was dissolved in ethyl acetate and theorganic layer was washed with saturated aqueous NaHCO₃ and dried overNa₂SO₄. This solution was filtered and the filtrate was concentrated invacuo. The crude was purified by flash chromatography (dichloromethaneto 10% MeOH in dichloromethane) to give 940 mg of the free base of thetitle compound.

This free base (886 mg) was converted to the hydrochloride salt (847 mg)according to the method described in Example 1. The title compound wasobtained as a white solid. Analytical Chiral HPLC confirmed the productto be identical to Enantiomer 2 of Example 16.

NMR and MS data corresponded to those reported for Example 16.

The absolute configuration of the title compound was confirmed usingcomparative VCD and comparative OR analyses of the corresponding freebase to be (1S,5R)-1-[2-fluoro-4-30(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane.(1S,5R)-3-(3-{[4-Methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane(see Example 14) was used as the reference.

Specific Optical Rotation of the corresponding free base: [α]_(D)=−42°(CDCl₃, T=25° C., c≅0.005 g/0.8 mL).

Examples 41-52

To a solution of the respective 3-thio-5-aryl-1,2,4-triazole (preparedin analogy to the method described in Preparation 13, 0.131 mmol) in dryacetonitrile (2 mL)2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diaza-phosphorineon polystyrene (90 mg, 2.2 mmol/g) was added and the resulting mixturewas shaken for 30 minutes at room temperature.(1S,5R)-3-(3-Chloropropyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane(40 mg) was added and the resulting mixture was shaken at 70° C. forthree hours. After cooling the resin was removed by filtration, washedwith methanol (2 mL), and then the solvent was removed under reducedpressure. Purifications were carried out using mass directed HPLC usinga Waters XTerra Prep MS C18 10 μm, 30×150 mm column using the followingconditions:

Time Flow % A % B Prerun 0 40 ml/min 99 1 1 40 ml/min 99 1 Run 0 40ml/min 99 1 10 40 ml/min 75 25 14.5 40 ml/min 10 90 15 40 ml/min 0 100Postrun 0 40 ml/min 0 100 0.2 45 ml/min 0 100 1.5 45 ml/min 0 100 2 40ml/min 0 100 A = H2O + 0.1% formic acid B = ACN + 0.1% formic acid

Then solvent was removed under reduced pressure to give the respectivecompounds as formate salts. The residues were taken up with methanol (1mL) and loaded on SCX SPE cartridges (1 g), washed with methanol (3 mL)and eluted with a 2 M ammonia solution in methanol (3 mL), then thesolvent was removed under reduced pressure. The residues were taken upwith dichloromethane (1 mL) and a 1.0 M HCl solution in diethylether wasadded (0.131 mmol), then the solvent was removed under reduced pressureto give product compounds summarised in TABLE 1 as hydrochloride salts.

Analytical Chromatographic Conditions: Column: X Terra MS C18 5 mm,50×4.6 mm

Mobile phase: A: NH4HCO3 sol. 10 mM, pH10; B: CH3CNGradient: 10% (B) for 1 min, from 10% (B) to 95% (B) in 12 min, 95% (B)for 3 minFlow rate: 1 mL/minUV wavelength range: 210-350 nmMass range: 100-900 amu

Ionization: ES+

TABLE 1 EX Name and Structure R (min) Analytical data 41

9.35 NMR (¹H, DMSO): δ 10.84 (bs, HCl), 8.77 (dd, 1H), 8.19 (bd, 1H),7.71 (d, 2H), 7.66 (m, 1H), 7.51 (d, 2H), 4.08 (dd, 1H), ca 3.8 (s, 3H),3.8-3.3 (m, 7H), 2.54 (s, 3H), 2.30 (m, 1H), 2.22 (m, 2H), 1.83 (m, 1H),1.20 (m, 1H). NMR (¹⁹F, DMSO): δ −60.8. MS (m/z): 474 [MH]⁺. 42

8.84 NMR (¹H, DMSO): δ 10.24 (bs, HCl), 9.56 (m, 1H), 9.39 (m, 1H), 8.01(s, 1H), 7.64 (m, 2H), 7.44 (m, 2H), 4.08 (m, 1H), 3.68 (s, 3H), 3.58(bm, 1H), 3.7-3.3 (m, 6H), 2.26 (m, 1H), 2.13 (m, 2H), 1.58 (t, 1H),1.14 (t, 1H). MS (m/z): 461 [MH]⁺. 43

9.27 MS (m/z): 477 [MH]⁺ 44

8.92 MS (m/z): 461 [MH]⁺ 45

10.72 NMR (¹H, DMSO): δ 10.56 (bs, HCl), 7.85 (d, 1H), 7.71 (d, 2H),7.51 (d, 2H), 6.64 (d, 1H), 4.08 (dd, 1H), 3.75 (dd, 1H), 3.71 (s, 3H),3.7-3.3 (m, 4H), 3.27 (t, 2H), 2.31 (m, 1H), 2.28 (s, 3H), 2.18 (m, 2H),1.74 (t, 1H), 1.21 (t, 1H). MS (m/z): 463 [MH]⁺. 46

9.47 MS (m/z): 474 [MH]⁺ 47

9.79 MS (m/z): 494 [MH]⁺ 48

10.15 NMR (¹H, DMSO): δ 10.41 (bs, HCl), 9.11 (bs, 1H), 8.63 (bs, 1H),7.66 (d, 2H), 7.44 (d, 2H), 4.02 (dd, 1H), 3.83 (s, 3H), 3.68 (d, 1H),3.6-3.2 (m, 6H), 2.54 (s, 3H), 2.25 (m, 1H), 2.14 (m, 2H), 1.65 (m, 1H),1.14 (m, 1H). MS (m/z): 475 [MH]⁺. 49

9.15 MS (m/z): 467 [MH]⁺ 50

10.17 NMR (¹H, DMSO): δ 10.41 (bs, HCl), 8.67 (bs, 1H), 8.47 (s, 1H),8.2 (s, 2H), 7.72 (m, 1H), 7.68 (m, 2H), 7.49 (m, 2H), 4.07 (m, 1H),3.74 (dd, 1H), 3.72 (s, 3H), 3.64 (dd, 1H), 3.51 (m, 1H), 3.3 (m, 4H),2.81 (s, 3H), 2.28 (m, 1H), 2.19 (m, 2H), 1.72 (t, 1H), 1.19 (t, 1H). MS(m/z): 524 [MH]⁺. 51

10.14 MS (m/z): 542 [MH]⁺ 52

10.12 MS (m/z): 524 [MH]⁺

Examples 53-58

To a solution of the respective 3-thio-5-aryl-1,2,4-triazole (0.124mmol) in dry acetonitrile (2 mL)2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diaza-phosphorineon polystyrene (85 mg, 2.2 mmol/g) was added and the resulting mixturewas shaken for 30 minutes at room temperature, then(1S,5R)-3-(3-chloropropyl)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane(40 mg) was added and the resulting mixture was shaken at 50° C.overnight. After cooling the resin was removed by filtration, washedwith methanol (2 mL) and then the solvent was removed under reducedpressure. Purifications were carried out using mass directed HPLC:

Preparative Chromatographic Conditions (Prep. HPLC of 6 Out of 6Compounds)

Column: X Terra MS C18 5 mm, 100×19 mm

Mobile phase: A: NH4HCO3 sol. 10 mM, pH10; B: CH3CNGradient: 30% (B) for 1 min, from 30% (B) to 95% (B) in 9 min, 95% (B)for 3 minFlow rate: 17 mL/minUV wavelength range: 210-350 nmMass range: 100-900 amu

Ionization: ES+

Then solvent was removed under reduced pressure to give compounds asfree bases. The residues were taken up with dichloromethane (2 mL) and a1.0 M HCl solution in diethylether was added (0.124 mmol) then solventwas removed under reduced pressure to give to give product compoundssummarised in TABLE 2 as hydrochloride salts.

Analytical Chromatographic Conditions Column: X Terra MS C18 5 mm,50×4.6 mm

Mobile phase: A: NH4HCO3 sol. 10 mM, pH10; B: CH3CNGradient: 30% (B) for 1 min, from 30% (B) to 95% (B) in 9 min, 95% (B)for 3 minFlow rate: 1 mL/minUV wavelength range: 210-350 nmMass range: 100-900 amu

Ionization: ES+

TABLE 2 Example Name and Structure R (min) Analytical data 53

6.58 NMR (¹H, DMSO): δ 10.64 (bs, HCl), 8.72 (dd, 1H), 8.05 (d, 1H),7.73 (d, 1H), 7.67 (t, 1H), 7.62 (d, 1H), 7.56 (dd, 1H), 4.01 (d, 1H),3.79 (d, 1H), 3.7-3.3 (m, 5H), 3.5-3.3 (2 x t, 4H), 2.57 (s, 3H), 2.46(m, 1H), 2.18 (m, 2H), 1.73 (t, 1H), 1.15 (t, 1H). MS (m/z): 492 [MH 54

6.09 NMR (¹H, DMSO): δ 10.66 (bs, HCl), 9.63 (m, 1H), 9.47 (dd, 1H),8.09 (dd, 1H), 7.73 (d, 1H), 7.67 (t, 1H), 7.62 (d, 1H), 3.99 (d, 1H),3.78 (d, 1H), 3.75 (s, 3H), 3.7-3.4 (m, 2H), 3.32 (m, 4H), 2.36 (m, 1H),2.17 (m, 2H), 1.74 (t, 1H), 1.14 (t, 1H). MS (m/z): 479 [MH 55

6.22 NMR (¹H, DMSO): δ 10.05 (bs, HCl), 9.38 (s, 1H), 9.19 (s, 2H), 7.74(d, 1H), 7.67 (t, 1H), 7.62 (d, 1H), 4.02 (bd, 1H), 3.81 (bd, 1H), 3.69(t, 3H), 3.58 (m, 1H), 3.5-3.2 (m, 5H), 2.38 (m, 1H), 2.16 (m, 2H), 1.55(t, 1H), 1.17 (t, 1H). 56

7.17 NMR (¹H, DMSO): δ 10.45 (bs, HCl), 7.73 (d, 1H), 7.67 (t, 1H), 7.62(d, 1H), 4.01 (d, 1H), 3.79 (d, 1H), 3.6-3.3 (m, 5H), 3.5-3.3 (t, 2H),3.28 (t, 2H), 2.70 (s, 3H), 2.37 (m, 1H), 2.34 (s, 3H), 2.16 (m, 2H),1.67 (t, 1H), 1.55 (t, 1H). MS (m/z): 512 [MH]⁺ 57

7.7 NMR (¹H, DMSO): δ 10.23 (bs, HCl), 9.17 (s, 1H), 8.70 (s, 1H), 7.73(d, 1H), 7.67 (t, 1H), 7.61 (d, 1H), 4.01 (d, 1H), 3.89 (s, 3H), 3.8 (d,1H), 3.6-3.3 (m, 2H), 3.5-3.2 (bm, 4H), 2.61 (s, 3H), 2.37 (m, 1H), 2.16(m, 2H), 1.61 (t, 1H), 1.16 (t, 1H). MS (m/z): 493 [MH 58

8.92 NMR (¹H, DMSO): δ 10.64 (bs, HCl), 7.98 (d, 2H), 7.95 (d, 2H), 7.73(d, 1H), 7.70 (t, 1H), 7.61 (d, 1H), 4.00 (d, 1H), 3.79 (d, 1H), 3.67(s, 3H), 3.55 (d, 1H), 3.45 (d, 1H), 3.34 (bm, 2H), 3.29 (t, 2H), 2.35(m, 1H), 2.17 (m, 2H), 1.73 (t, 1H), 1.14 (t, 1H). MS (m/z): 545 [MH

Example 591-{4-[(1R,5S/1S,5R)-3-(3-{[4-Methyl-5-(2-methyl-5-quinolinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]phenyl}-2-pyrrolidinonehydrochloride

A Schlenk tube was charged with5-[5-({3-[(1R,5S/1S,5R)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]hex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazol-3-yl]-2-methylquinoline(cf. Example 2; 0.15 g), 2-pyrrolidinone (32 mg),tris(dibenzylideneacetone)-dipalladium(0) (6 mg),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (10 mg), cesiumcarbonate (130 mg) and 1,4-dioxane (2 mL). The Schlenk tube was sealedwith a teflon screwcap and the reaction mixture was stirred at 100° C.for 12 h. The reaction mixture was allowed to cool to room temperature,diluted with dichloromethane (10 mL), filtered and concentrated invacuo. The crude product was purified by flash chromatography(dichloromethane to 10% MeOH in dichloromethane) to give 60 mg of thefree base of the title compound. To a solution of this material indichloromethane (0.4 mL) was added HCl (0.11 mL, 1M in Et₂O), thesolvent evaporated in vacuo and the material thus obtained trituratedwith Et₂O to give 64 mg of the title compound as a white solid.

NMR (¹H, DMSO): δ 10.48 (bs, 1H), 8.24 (bd, 1H), 8.18 (d, 1H), 7.93 (t,1H), 7.81 (d, 1H), 7.62 (d, 2H), 7.54 (d, 1H), 7.31 (d, 2H), 4.04 (dd,1H), 3.82 (t, 2H), 3.76 (dd, 1H), 3.70/3.10 (bm, 8H), 3.45 (s, 3H), 2.74(s, 3H), 2.25 (m, 2H), 2.16 (m, 1H), 2.07 (m, 2H), 1.63/1.10 (t/t, 2H).MS (m/z): 539 [MH]⁺.

Example 605-{5-[(3-{(1R,5S/1S,5R)-1-[4-(1,1-Dioxido-2-isothiazolidinyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)thio]-4-methyl-4H-1,2,4-triazol-3-yl}-2-methylquinolinehydrochloride

A Schlenk tube was charged with5-[5-({3-[(1R,5S/1S,5R)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]hex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazol-3-yl]-2-methylquinoline(cf. Example 2; 0.15 g), isothiazolidine 1,1-dioxide (46 mg),tris(dibenzylideneacetone)-dipalladium(0) (6 mg),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (10 mg), cesiumcarbonate (130 mg) and 1,4-dioxane (2 mL). The Schlenk tube was sealedwith a teflon screwcap and the reaction mixture was stirred at 100° C.for 12 h. The reaction mixture was allowed to cool to room temperature,diluted with dichloromethane (10 mL), filtered and concentrated invacuo. The crude product was purified by flash chromatography(dichloromethane to 10% MeOH in dichloromethane) to give 50 mg of thefree base of the title compound. To a solution of this material indichloromethane (0.3 mL) was added HCl (0.087 mL, 1M in Et₂O), thesolvent evaporated in vacuo and the material thus obtained trituratedwith Et₂O to give 52 mg of the title compound as a white solid.

NMR (¹H, DMSO): δ 10.57 (bs, 1H), 8.27 (bd, 1H), 8.19 (d, 1H), 7.94 (t,1H), 7.82 (d, 1H), 7.55 (d, 1H), 7.32 (d, 2H), 7.18 (d, 2H), 4.03 (dd,1H), 3.72 (m, 3H), 3.60/3.20 (bm, 8H), 3.45 (s, 3H), 2.75 (s, 3H), 2.41(m, 2H), 2.25 (m, 2H), 2.14 (m, 1H), 1.66/1.10 (t/m, 2H). MS (m/z): 575[MH]⁺.

Example 61(1R,5S/1S,5R)-1-[3-Fluoro-4-(trifluoromethyl)phenyl]-5-methyl-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexanehydrochloride

The title compound was prepared in analogy to the method described inExample 1 in 247 mg yield as a white slightly hygroscopic solid from(1R,5S/1S,5R)-1-[3-fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane(338 mg).

NMR (¹H, CD3OD): δ 8.4 (s, 1H), 7.55 (t, 1H), 7.37 (d, 1H), 7.32 (d,1H), 4.2 (d, 1H), 3.91 (d, 1H), 3.81 (s, 3H), 3.76 (d, 1H), 3.67 (d,1H), 3.51 (t, 2H), 3.43 (t, 2H), 2.47 (s, 3H), 2.41 (m, 1H), 2.31 (m,2H), 1.61 (t, 1H), 1.45 (t, 1H). MS (m/z): 496 [MH]⁺.

Example 61 was separated to give the separated enantiomers bysemipreparative Supercritical Fluid Chromatography (Gilson) using achiral column Chiralpak AD-H, 25×2.1 cm, eluent CO₂ containing 12%(Ethanol+0.1% isopropylamine), flow rate 22 mL/min, P 194 bar, T 36° C.,detection UV at 220 nm. Retention times given were obtained using ananalytical Supercritical Fluid Chromatography (Berger) using a chiralcolumn Chiralpak AD-H, 25×0.46 cm, eluent CO₂ containing 10%(ethanol+0.1% isopropylamine), flow rate 2.5 mL/min, P 180 bar, T 35°C., detection UV at 220 nm.

Enantiomer 1 was recovered in 42 mg yield as white solid, hydrochloridesalt from the racemate (100 mg). Rt.=27.1 min. Purity 100% a/a by UV.

Enantiomer 2 was recovered in 34 mg yield as white solid, hydrochloridesalt from the racemate (100 mg). Rt.=31.0 min. Purity 100% a/a by UV.Enantiomer 1 showed fpKi (D3)>2 log-unit higher than Enantiomer 2.

Example 621-(2-(Methyloxy)-5-{(1R,5S/1S,5R)-3-[3-({4-methyl-5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}thio)propyl]-3-azabicyclo[3.1.0]hex-1-yl}phenyl)ethanonehydrochloride

The title compound was prepared in analogy to the method described inExample 1 in 51 mg yield as a white solid (y=60%) from1-[5-[(1R,5S/1S,5R)-3-azabicyclo[3.1.0]hex-1-yl]-2-(methyloxy)phenyl]ethanone(35 mg) and3-[(3-chloropropyl)thio]-4-methyl-5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazole(60 mg, prepared in analogy to the method described in Preparation 13).

NMR (¹H, CDCl₃, free base): δ 7.80-7.70 (m, 4H), 7.50 (s, 1H), 7.27-7.20(m, 1H), 6.85 (d, 1H), 3.86 (s, 3H), 3.62 (s, 3H), 3.40-3.24 (m, 3H),3.15 (d, 1H), 2.58 (s, 3H), 2.65-2.55 (m, 2H), 2.54-2.45 (m, 2H),2.10-1.90 (quint, 2H), 1.65-1.57 (m, 1H), 1.35 (m, 1H), 0.75 (m, 1H). MS(m/z): 531 [MH]⁺.

Example 631-[5-[(1R,5S/1S,5R)-3-(3-{[5-(3,4-Difluorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]-2-(methyloxy)phenyl]ethanonehydrochloride

The title compound was prepared in analogy to the method described inExample 1 in 40 mg yield as a white solid (y=50%) from1-[5-[(1R,5S/1S,5R)-3-azabicyclo[3.1.0]hex-1-yl]-2-(methyloxy)phenyl]ethanone(35 mg) and3-[(3-chloropropyl)thio]-5-(3,4-difluorophenyl)-4-methyl-4H-1,2,4-triazole(54 mg, prepared in analogy to the method described in Preparation 13).

NMR (¹H, CDCl₃, free base): δ 7.56-7.19 (m, 5H), 6.84 (d, 1H), 3.86 (s,3H), 3.62 (s, 3H), 3.38-3.24 (m, 3H), 3.10 (d, 1H), 2.58 (s, 3H),2.65-2.42 (m, 4H), 2.10-1.90 (quint, 2H), 1.65-1.57 (m, 1H), 1.35 (m,1H), 0.75 (m, 1H). MS (m/z): 499 [MH]⁺.

Example 641-{2-(Methyloxy)-5-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]phenyl}ethanonehydrochloride

The title compound was prepared in analogy to the method described inExample 1 in 32 mg yield as a yellow solid (y=42%) from1-[5-[(1R,5S/1S,5R)-3-azabicyclo[3.1.0]hex-1-yl]-2-(methyloxy)phenyl]ethanone(35 mg) and3-{5-[(3-chloropropyl)thio]-4-methyl-4H-1,2,4-triazol-3-yl}pyridine (48mg, prepared in analogy to the method described in Preparation 13).

NMR (¹H, CDCl₃, free base): δ 8.87 (s, 1H), 8.70 (d, 1H), 8.0 (d, 1H),7.48 (s, 1H), 7.43 (m, 1H), 7.23 (m, 1H), 6.84 (d, 1H), 3.86 (s, 3H),3.62 (s, 3H), 3.40-3.25 (m, 3H), 3.10 (d, 1H), 2.58 (s, 3H), 2.67-2.42(m, 4H), 2.10-1.90 (quint, 2H), 1.65-1.57 (m, 1H), 1.35 (m, 1H), 0.75(m, 1H). MS (m/z): 464 [MH]⁺.

Example 651-[5-[(1R,5S/1S,5R)-3-(3-{[4-Methyl-5-(2-methyl-5-quinolinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]-2-(methyloxy)phenyl]ethanonehydrochloride

The title compound was prepared in analogy to the method described inExample 1 in 50 mg yield as a yellow solid (y=60%) from1-[5-[(1R,5S/1S,5R)-3-azabicyclo[3.1.0]hex-1-yl]-2-(methyloxy)phenyl]ethanone(35 mg) and5-{5-[(3-chloropropyl)thio]-4-methyl-4H-1,2,4-triazol-3-yl}-2-methylquinoline(60 mg).

NMR (¹H, DMSO): δ 10.38 (bs, 1H), 8.2 (m, 2H), 7.91 (t, 1H), 7.78 (d,1H), 7.5 (m, 3H), 7.17 (d, 1H), 4.02 (d, 1H), 3.89 (s, 3H), 3.74 (dd,1H), 3.6-3.2 (m, 6H), 3.45 (s, 3H), 2.72 (s, 3H), 2.5 (s, 3H), 2.23(quint, 2H), 2.11 (quint, 1H), 1.57 (t, 1H), 1.1 (t, 1H). MS (m/z): 528[MH]⁺.

Example 661-{2-(Methyloxy)-5-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]phenyl}ethanonehydrochloride

The title compound was prepared in analogy to the method described inExample 1 in 24 mg yield as a white solid (y=32%) from1-[5-[(1R,5S/1S,5R)-3-azabicyclo[3.1.0]hex-1-yl]-2-(methyloxy)phenyl]ethanone(35 mg) and3-[(3-chloropropyl)thio]-4-methyl-5-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazole(50 mg, prepared in analogy to the method described in Preparation 13).

NMR (¹H, CDCl₃, free base): δ 7.49 (s, 1H), 7.24 (m, 1H), 6.85 (d, 1H),4.14-4.05 (m, 2H), 3.86 (s, 3H), 3.62 (s, 3H), 3.57-3.40 (m, 2H),3.29-3.15 (m, 3H), 3.05 (d, 1H), 2.82-2.95 (m, 1H), 2.63-2.40 (m, 4H),2.58 (s, 3H), 2.15-1.77 (m, 6H), 1.62 (m, 1H), 1.32 (m, 1H), 0.70 (m,1H). MS (m/z): 471 [MH]⁺.

Example 671-(2-Hydroxy-5-{(1R,5S/1S,5R)-3-[3-({4-methyl-5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}thio)propyl]-3-azabicyclo[3.1.0]hex-1-yl}phenyl)ethanonehydrochloride

The title compound was prepared in analogy to the method described inExample 1 in 35 mg yield as a white solid (y=33%) from1-{5-[(1R,5S/1S,5R)-3-azabicyclo[3.1.0]hex-1-yl]2-hydroxyphenyl}ethanone(43 mg) and3-[(3-chloropropyl)thio]-4-methyl-5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazole(80 mg, prepared in analogy to the method described in Preparation 13).

NMR (¹H, CDCl₃, free base): δ 12.2 (s, 1H), 7.80-7.70 (m, 4H), 7.50 (s,1H), 7.30 (m, 1H), 6.88 (d, 1H), 3.86 (s, 3H), 3.40-3.25 (m, 3H), 3.10(d, 1H), 2.58 (s, 3H), 2.65-2.35 (m, 4H), 2.0 (quint, 2H), 1.58 (m, 1H),1.35 (m, 1H), 0.70 (m, 1H). MS (m/z): 517 [MH]⁺.

Example 681-{5-[(1R,5S/1S,5R)-3-(3-{[5-(3,4-Difluorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]-2-hydroxyphenyl}ethanonehydrochloride

The title compound was prepared in analogy to the method described inExample 1 in 27 mg yield as a white solid (y=29%) from1-{5-[(1R,5S/1S,5R)-3-azabicyclo[3.1.0]hex-1-yl]-2-hydroxyphenyl}ethanone(40 mg) and3-[(3-chloropropyl)thio]-5-(3,4-difluorophenyl)-4-methyl-4H-1,2,4-triazole(67 mg, prepared in analogy to the method described in Preparation 13).

NMR (¹H, DMSO): δ 11.82 (s, 1H), 10.26 (bs, 1H), 7.85 (m, 1H), 7.76 (d,1H), 7.67 (m, 1H), 7.61 (m, 1H), 7.51 (dd, 1H), 6.97 (d, 1H), 4.02 (dd,1H), 3.74 (dd, 1H), 3.64 (s, 3H), 3.55 (m, 2H), 3.3 (m, 4H), 2.67 (s,3H), 2.15 (m, 3H), 1.52 (t, 1H), 1.13 (t, 1H). MS (m/z): 485 [MH]⁺.

Example 691-{2-Hydroxy-5-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]phenyl}ethanonehydrochloride

The title compound was prepared in analogy to the method described inExample 1 in 36 mg yield as a white solid (y=43%) from1-{5-[(1R,5S/1S,5R)-3-azabicyclo[3.1.0]hex-1-yl]-2-hydroxyphenyl}ethanone(38 mg) and3-[(3-chloropropyl)thio]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole(57 mg).

NMR (¹H, CDCl₃, free base): δ 12.2 (s, 1H), 7.88 (s, 1H), 7.50 (s, 1H),7.24 (m, 1H), 6.58 (d, 1H), 3.68 (s, 3H), 3.32 (m, 3H), 3.10 (d, 1H),2.58-2.47 (m, 4H), 2.58 (s, 3H), 2.47 (s, 3H), 2.0 (m, 2H), 1.62 (m,1H), 1.35 (m, 1H), 0.68 (m, 1H). MS (m/z): 454 [MH]⁺.

Example 701-{2-Hydroxy-5-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(2-methyl-5-quinolinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]phenyl}ethanonehydrochloride

The title compound was prepared in analogy to the method described inExample 1 in 24 mg yield as a yellow solid (y=32%) from1-{5-[(1R,5S/1S,5R)-3-azabicyclo[3.1.0]hex-1-yl]-2-hydroxyphenyl}ethanone(30 mg) and5-{5-[(3-Chloropropyl)thio]-4-methyl-4H-1,2,4-triazol-3-yl}-2-methylquinoline(55 mg).

NMR (¹H, CDCl₃, free base): δ 12.1 (s, 1H), 8.10 (dd, 2H), 7.67 (t, 1H),7.50 (m, 2H), 7.23 (m, 2H), 6.85 (d, 1H), 3.45-3.23 (m, 3H), 3.40 (s,3H), 3.08 (d, 1H), 2.67 (s, 3H), 2.65-2.41 (m, 4H), 2.55 (s, 3H), 2.02(m, 2H), 1.58 (m, 1H), 1.32 (m, 1H), 0.64 (m, 1H). MS (m/z): 514 [MH]⁺.

Example 711-[5-[(1R,5S/1S,5R)-3-(3-{[4-Methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]-2-(methyloxy)phenyl]-1-propanonehydrochloride

The title compound was prepared in analogy to the method described inExample 1 in 51 mg yield as a white solid (y=47%) from1-[5-[(1R,5S)-3-azabicyclo[3.1.0]hex-1-yl]-2-(methyloxy)phenyl]-1-propanone(52 mg, prepared in analogy to the method described in Preparations43-45) and3-[(3-chloropropyl)thio]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole(69 mg).

NMR (¹H, DMSO): δ 10.24 (bs, 1H), 8.52 (m, 1H), 7.42 (d, 1H), 7.40 (dd,1H), 7.08 (d, 1H), 3.93 (dd, 1H), 3.81 (s, 3H), 3.67 (dd, 1H), 3.64 (s,3H), 3.48 (m, 2H), 3.28 (m, 2H), 3.22 (t, 2H), 2.86 (q, 2H), 2.33 (s,3H), 2.1 (m, 2H), 2.03 (m, 1H), 1.48 (t, 1H), 1.0 (t, 1H), 1.04 (t, 3H).MS (m/z): 482 [MH]⁺.

The title compound was separated to give the separated enantiomers bysemi-preparative HPLC using a chiral column chiralpak AS-H 5 μm, 250×21mm, eluent A: n-hexane; B: ethanol+0.1% isopropylamine, gradientisocratic 40% B, flow rate 7 mL/min, detection UV at 200-400 nm.Retention times given were obtained using an analytical HPLC using achiral column chiralpak AS-H 5 μm, 250×4.6 mm, eluent A: n-hexane; B:ethanol+0.1% isopropylamine, gradient isocratic 40% B, flow rate 0.8mL/min, detection UV at 200-400 nm.

Enantiomer 1 was recovered in 10 mg yield as white solid (y=30%) fromthe racemate (66 mg). Rt.=17.2 min.

Enantiomer 2 was recovered in 10 mg yield as white solid (y=30%) fromthe racemate (66 mg). Rt.=19.1 min.

Enantiomer 1 showed fpKi (D3)>1 log-unit higher than Enantiomer 2.

Example 722-Methyl-5-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]-1,3-benzothiazolehydrochloride

5-[(1R,5S)-3-Azabicyclo[3.1.0]hex-1-yl]-2-methyl-1,3-benzothiazole wasprepared from 2-methyl-1,3-benzothiazol-5-amine dihydrochloride inanalogy to the method described in Preparations 15, 16 and 17. From thismaterial the title compound was obtained as a yellow solid following themethod described for Examples 14 and 15.

NMR (¹H, DMSO): δ 10.54 (bs, 1H), 8.58 (m, 1H), 8.0 (d, 1H), 7.9 (d,1H), 7.34 (dd, 1H), 4.0 (dd, 1H), 3.75 (dd, 1H), 3.70 (s, 3H), 3.65 (m,1H), 3.57 (m, 1H), 3.35 (m, 2H), 3.30 (t, 2H), 2.8 (s, 3H), 2.39 (s,3H), 2.27 (m, 1H), 2.19 (m, 2H), 1.7 (t, 1H), 1.19 (t, 1H). MS (m/z):467 [MH]⁺.

The title compound was separated to give the separated enantiomers bysemi-preparative HPLC using a chiral column chiralpak AS-H 5 μm, 250×21mm, eluent A: n-hexane; B: ethanol+0.1% isopropylamine, gradientisocratic 13% B, flow rate 7 mL/min, detection UV at 200-400 nm.Retention times given were obtained using an analytical HPLC using achiral column chiralpak AS-H 5 μm, 250×4.6 mm, eluent A: n-hexane; B:ethanol+0.1% isopropylamine, gradient isocratic 13% B, flow rate 1mL/min, detection UV at 200-400 nm.

Enantiomer 1 was recovered in 17 mg yield as white solid (y=62%) fromthe racemate (55 mg). Rt.=17.1 min.

Enantiomer 2 was recovered in 18 mg yield as white solid (y=65%) fromthe racemate (55 mg). Rt.=19.3 min.

Enantiomer 1 showed fpKi (D3)>1 log-unit higher than Enantiomer 2.

Example 732-Methyl-6-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]-1,3-benzothiazolehydrochloride

6-[(1R,5S/1S,5R)-3-Azabicyclo[3.1.0]hex-1-yl]-2-methyl-1,3-benzothiazolewas prepared from 2-methyl-1,3-benzothiazol-6-amine in analogy to themethod described in Preparations 15, 16 and 5. From this material thetitle compound was obtained as a yellow solid following the methoddescribed for Examples 14 and 15.

NMR (¹H, CD₃OD): δ 8.39 (s, 1H), 7.98 (d, 1H), 7.89 (d, 1H), 7.5 (dd,1H), 4.19 (d, 1H), 3.92 (d, 1H), 3.8 (s, 3H), 3.72 (d, 2H), 3.52 (t,2H), 3.42 (t, 2H), 2.85 (s, 3H), 2.47 (s, 3H), 2.31 (m, 3H), 1.54 (t,1H), 1.41 (t, 1H). MS (m/z): 467 [MH]⁺.

Example 741-Methyl-5-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hex-1-yl]-1H-indazolehydrochloride

5-[(1R,5S/1S,5R)-3-Azabicyclo[3.1.0]hex-1-yl]-1-methyl-1H-indazole wasprepared from 1-methyl-1H-indazol-5-amine in analogy to the methoddescribed in Preparations 15, 16 and 5. From this material the titlecompound was obtained as a yellow solid following the method describedfor Examples 14 and 15.

NMR (¹H, DMSO): δ 10.4 (bs, 1H), 8.58 (m, 1H), 8.01 (s, 1H), 7.70 (d,1H), 7.63 (d, 1H), 7.39 (dd, 1H), 4.05 (m, 1H), 4.04 (s, 3H), 3.75 (d,1H), 3.70 (s, 3H), 3.59 (m, 2H), 3.39 (t, 2H), 3.26 (t, 2H), 2.39 (s,3H), 2.18 (m, 3H), 1.61 (t, 1H), 1.14 (t, 1H). MS (m/z): 450 [MH]⁺.

The title compound was separated to give the separated enantiomers bysemi-preparative SFC (Gilson) using a chiral column chiralpak AS-H,250×21 mm, modifier: ethanol+0.1% isopropylamine 12%, flow rate 22mL/min, P 200 bar, T 36° C., detection UV at 220 nm. Retention timesgiven were obtained using an analytical SFC (Berger) using a chiralcolumn chiralpak AS-H 5 μm, 250×46 mm, modifier: ethanol+0.1%isopropylamine 12%, flow rate 2.5 mL/min, P 180 bar, T 35° C., detectionUV at 220 nm.

Enantiomer 1 was recovered in 25 mg yield as white solid (y=62%) fromthe racemate (80 mg). Rt.=19.5 min.

Enantiomer 2 was recovered in 28 mg yield as white solid (y=70%) fromthe racemate (80 mg). Rt.=22.8 min.

Enantiomer 1 showed fpKi (D3)>1 log-unit higher than Enantiomer 2.

Example 75(1R,5S/1S,5R)-3-(3-{[4-Methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexanehydrochloride

(1R,5S/1S,5R)-1-[6-(Trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane was prepared from6-(trifluoromethyl)-3-pyridinamine in analogy to the method described inPreparations 37 and 5. From this material the title compound wasobtained as a yellow solid following the method described for Examples14 and 15.

NMR (¹H, DMSO): δ 10.46 (bs, 1H), 8.73 (bs, 1H), 8.58 (m, 1H), 8.0 (dd,1H), 7.90 (d, 1H), 4.12 (m, 1H), 3.78 (d, 1H), 3.70 (s, 3H), 3.7 (m,1H), 3.54 (m, 1H), 3.39 (t, 2H), 3.29 (s, 2H), 2.39 (m, 3H), 2.47 (m,1H), 2.18 (m, 2H), 1.71 (m, 1H), 1.33 (m, 1H). NMR (19F, DMSO): δ −66.2(s). MS (m/z): 465 [MH]⁺.

Examples 76-94

To a solution of the respective 3-thio-5-aryl-1,2,4-triazole (preparedin analogy to the method described in Preparation 13, 0.063 mmol) in dryacetonitrile (2 mL)2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diaza-phosphorineon polystyrene (43 mg, 2.2 mmol/g) was added and the resulting mixturewas shaken for 1 h at room temperature, then(1R,5S/1S,5R)-1-(4-bromophenyl)-3-(3-chloropropyl)-3-azabicycle-[3.1.0]hexane(20 mg) was added and the resulting mixture was shaken at 70° C. for 3.5hours. After cooling the resin was removed by filtration, washed withdichloromethane (2 mL) and methanol (2 mL) and the collected liquidphase was evaporated under reduced pressure. Two isomers were formed byS- and N-alkylation, the major isomer being the desired S-alkylated.Those isomers were separated using mass directed HPLC using a WatersXTerra Prep MS C18 10 μm. 30×150 mm column using the followingconditions:

Time Flow % A % B Prerun 0 40 ml/min 99 1 1 40 ml/min 99 1 Run 0 40ml/min 99 1 10 40 ml/min 75 25 14.5 40 ml/min 10 90 15 40 ml/min 0 100Postrun 0 40 ml/min 0 100 0.2 45 ml/min 0 100 1.5 45 ml/min 0 100 2 40ml/min 0 100 A = H2O + 0.1% formic acid B = acetonitrile + 0.1% formicacid

Then solvent was removed under reduced pressure to give title compoundsas formate salts.

In the case of Examples 93 and 94 the isomers were separated by silicagel flash chromatography. The S-alkylated isomers were dissolved in drydiethyl ether and cooled at 0° C. 1.2 eq of HCl (as 1.0 M solution indiethyl ether) were slowly added. The resulting precipitate wasdecanted, washed with pentane and filtered, yielding the products as thehydrochloride salts.

Analytical Conditions Examples 76-90

Column X-Terra MS C18 5 um, 50 × 4.6 mm Mobile Phase A: H20 + 0.1% TFA;B: CH3CN + 0.1% TFA Gradient 10% (B) for 1 min; from 10% (B) to 90% (B)in 12 min; 90% (B) for 3 min Flow rate 1 mL/min UV wavelength 200-400 nmrange Mass range 100-900 amu Ionisation ES+

Example 91

Column X-Terra MS C18 5 um, 50 × 4.6 mm Mobile Phase A: H20 + 0.2%HCOOH; B: CH3CN + 0.2% HCOOH Gradient 10% (B) for 1 min; from 10% (B) to95% (B) in 12 min; 95% (B) for 3 min Flow rate 1 mL/min UV wavelength210-400 nm range Mass range 100-900 amu Ionisation ES+

Example 93

Analytical Column ZORBAX SB C18, 50 mm, 4.6 mm i.d.; 1.8 um

Mobile phase Amm.Acet., 5 mM/Acetonitrile+0.1% Formic Acid

Gradient 97/3>36/64 v/v in 3.5 min>0/100 v/v in 3.5 min

Flow rate 2 mL/min

Detection DAD, 210-350 nm

MS ES+

Retention time 2.42 min

[M+H]+ 484/486 (1Br pattern)

Assay 98.17% a/a (by DAD)

Example 94

Analytical Column ZORBAX SB C18, 50 mm, 4.6 mm i.d.; 1.8 um

Mobile phase Amm.Acet., 5 mM/ Acetonitrile+0.1% Formic Acid

Gradient 97/3>36/64 v/v in 3.5 min>0/100 v/v in 3.5 min

Flow rate 2 mL/min

Detection DAD, 210-350 nm

MS ES+

Retention time 3.02 min

[M+H]+ 552/554 (1Br pattern)

Assay 99.51% a/a (by DAD)

Example Name and Structure R (min) Analytical data 76

5.92 NMR (¹H, DMSO): δ 8.6 (d, 1H), 8.2 (s, HCOOH), 7.9 (d, 1H), 7.5 (d,2H), 7.4 (dd, 1H), 7.1 (d, 2H), 3.4 (s, 3H), 3.4 (m, 1H + water), 3.25(t, 2H), 3.05 (d, 1H), 2.6 (m, 1H), 2.5 (m, 2H + DMSO), 2.4 (m, 1H), 2.4(s, 3H), 1.9 (m, 2H), 1.8 (m, 1H), 1.4 (m, 1H), 0.8 (m, 1H). MS (m/z):484, 486 [MH]⁺. 77

6.42 NMR (¹H, DMSO): δ 9.6 (d, 1H), 8.2 (s, HCOOH), 9.4 (dd, 1H), 8.1(d, 1H), 7.45 (d, 2H), 7.1 (d, 2H), 3.75 (s, 3H), 3.3 (m, 1H), 2.25 (t,2H), 3.05 (d, 1H), 2.6 (t, 2H), 2.5 (d, 1H + DMSO), 2.4 (m, 1H), 1.9 (m,2H), 1.8 (m, 1H), 1.4 (m, 1H), 0.75 (m, 1H). MS (m/z): 471, 473 [MH]⁺.78

6.94 NMR (¹H, DMSO): δ 8.2 (s, HCOOH), 8.0 (s, 1H), 7.45 (d, 2H), 7.1(d, 2H), 3.9 (s, 3H), 3.55 (s, 3H), 3.3 (m, 1H + water), 3.2 (t, 2H),3.0 (m, 1H), 2.6 (t, 2H), 2.5 (m, 1H), 2.4 (m, 1H), 2.85 (m, 2H), 2.8(m, 1H), 1.4 (m, 1H), 0.75 (m, 1H). MS (m/z): 507, 509 [MH]⁺. 79

6.64 NMR (¹H, DMSO): δ 8.7 (s, 1H), 8.2 (s, HCOOH), 7.45 (d, 2H), 7.1(d, 2H), 4.2 (s, 3H), 3.85 (s, 3H), 3.3 (m, 1H), 3.2 (t, 2H), 3.05 (m,1H), 2.6 (t, 2H), 2.45 (m, 1H), 2.4 (m, 1H), 2.9 (m, 2H), 2.8 (m, 1H),1.35 (m, 1H), 0.75 (m, 1H). MS (m/z): 474, 476 [MH]⁺. 80

6.62 NMR (¹H, DMSO): δ 8.2 (s, HCOOH), 7.8 (s, 1H), 7.45 (d, 2H), 7.1(d, 2H), 3.85 (s, 3H), 3.6 (s, 3H), 3.3 (m, 1H + DMSO), 3.2 (t, 2H), 3.0(d, 1H), 2.6 (t, 2H), 2.5 (m, 1H), 2.4 (s, 3H), 2.4 (m, 1H), 1.85 (m,3H), 1.4 (m, 1H), 0.75 (m, 1H). MS (m/z): 487, 489 [MH]⁺. 81

6.39 NMR (¹H, DMSO): δ 9.4 (d, 1H), 9.2 (d, 2H), 8.2 (s, HCOOH), 7.45(d, 2H), 7.1 (d, 2H), 3.7 (s, 3H), 3.3 (m, 1H + DMSO), 3.2 (t, 2H), 3.1(m, 1H), 2.6 (t, 2H), 2.5 (m, 1H), 2.4 (m, 1H), 1.9 (t, 2H), 1.8 (m,1H), 1.4 (m, 1H), 0.75 (m, 1H). MS (m/z): 471, 473 [MH]⁺. 82

7.67 NMR (¹H, DMSO): δ 8.4 (s, 1H), 8.2 (s, HCOOH), 7.45 (d, 2H), 7.1(d, 2H), 4.05 (s, 3H), 3.45 (s, 3H), 3.3 (m, 1H + water), 3.2 (t, 2H),3.0 (m, 1H), 2.6 (m, 2H), 2.45 (m, 1H), 2.4 (m, 1H), 2.85 (m, 3H), 1.4(m, 1H), 0.75 (m, 1H). MS (m/z): 541, 543 [MH]⁺. 83

7.82 NMR (¹H, DMSO): δ 8.2 (s, HCOOH), 7.85 (d, 1H), 7.45 (d, 2H), 7.1(d, 2H), 6.6 (d, 1h), 3.7 (s, 3H), 3.3 (m, 1H + water), 3.2 (t, 2H), 3.1(m, 1H), 2.6 (m, 2H), 2.5 (m, 1H), 2.4 (m, 1H), 2.3 (s, 3H), 1.9 (m,3H), 1.4 (m, 1H), 0.8 (m, 1H). MS (m/z): 473, 475 [MH]⁺. 84

7.22 NMR (¹H, DMSO): δ 8.2 (s, HCOOH), 7.45 (d, 2H), 7.1 (d, 2H), 7.0(s, 1H), 3.8 (s, 3H), 3.3 (m, 1H + water), 3.2 (t, 2H), 3.0 (m, 1H), 2.6(t, 2H), 2.5 (m, 1H), 2.4 (m, 1H), 2.4 (s, 3H), 1.9 (m, 2H), 1.8 (m,1H), 1.35 (m, 1H), 0.75 (m, 1H). MS (m/z): 474, 476 [MH]⁺. 85

5.94 NMR (¹H, DMSO): δ 8.8 (d, 1H), 8.2 (s, HCOOH), 8.0 (dd, 1H), 7.45(d, 2H), 7.45 (d, 1H), 7.1 (d, 2H), 3.6 (s, 3H), 3.3 (m, 1H + water),3.2 (t, 2H), 3.05 (m, 1H), 2.6 (m, 2H), 2.6 (s, 3H), 2.5 (m, 1H + DMSO),2.4 (m, 1H), 1.9 (m, 2H), 1.8 (m, 1H), 1.4 (m, 1H), 0.75 (m, 1H). MS(m/z): 484, 484 [MH]⁺. 86

6.87 NMR (¹H, DMSO): δ 8.2 (s, HCOOH), 7.6 (d, 1H), 7.45 (d, 2H), 7.1(d, 2H), 6.8 (d, 2H), 4.0 (s, 3H), 3.6 (s, 3H), 3.3 (m, 1H + water), 3.2(t, 2H), 3.1 (m, 1H), 2.6 (t, 2H), 2.5 (m, 1H + DMSO), 2.4 (m, 1H), 1.9(m, 2H), 1.8 (m, 1H), 1.4 (m, 1H), 0.75 (m, 1H). MS (m/z): 473, 475[MH]⁺. 87

6.09 NMR (¹H, DMSO): δ 8.75 (dd, 1H), 8.6 (dd, 1H), 8.2 (s, HCOOH), 8.0(dd, 1H), 7.45 (d, 2H), 7.1 (d, 2H), 3.6 (s, 3H), 3.3 (m, 1H + water),3.2 (t, 2H), 3.05 (m, 1H), 2.6 (t, 2H), 2.5 (m, 1H), 2.4 (m, 1H), 2.4(s, 3H), 1.9 (m, 2H), 1.8 (m, 1H), 1.4 (m, 1H), 0.75 (m, 1H). MS (m/z):484, 486 [MH]⁺. 88

8.12 NMR (¹H, DMSO): δ 8.2 (s, HCOOH), 7.45 (d, 2H), 7.1 (d, 2H), 3.7(s, 3H), 3.3 (m, 1H), 3.2 (t, 2H), 3.05 (m, 1H), 2.65 (t, 3H), 2.6 (t,2H), 2.5 (m, 1H), 2.4 (m, 1H), 1.9 (m, 2H), 1.8 (m, 1H), 1.35 (m, 1H),0.75 (m, 1H). MS (m/z): 542, 544 [MH]⁺. 89

7.17 NMR (¹H, DMSO): δ 9.6 (dd, 1H), 8.2 (s, HCOOH), 7.9 (dd, 1H), 7.45(dd, 1H), 7.45 (d, 2H), 7.1 (d, 2H), 3.6 (s, 3H), 3.3 (m, 1H), 3.2 (t,2H), 3.05 (m, 1H), 2.6 (t, 2H), 2.5 (m, 1H), 2.5 (s, 3H), 2.4, m, 1H),1.9 (m, 2H), 1.8 (m, 1H), 1.4 (m, 1H0, 0.75 (m, 1H). MS (m/z): 484, 486[MH]⁺. 90

6.96 NMR (¹H, DMSO): δ 8.2 (s, HCOOH), 7.45 (d, 2H), 7.1 (d, 2H), 3.5(s, 3H), 3.3 (m, 1H + water), 3.2 (t, 2H), 3.0 (m, 1H), 2.75 (s, 3H),2.6 (t, 2H), 2.5 (m, 1H), 2.4 (m, 1H), 2.3 (s, 3H), 1.9 (m, 2H), 1.8 (m,1H), 1.35 (m, 1H), 0.75 (m, 1H). MS (m/z): 504, 506 [MH]⁺. 91

8.33 NMR (¹H, DMSO): δ 8.2 (s, HCOOH), 7.45 (d, 2H), 7.1 (d, 2H), 6.4(s, 1H), 3.5 (s, 3H), 3.3 (m, 1H), 3.2 (t, 2H), 3.1 (m, 1H), 2.6 (t,2H), 2.5 (m, 1H), 2.4 (m, 1H), 2.4 (s, 3H), 2.3 (s, 3H), 1.85 (m, 3H),1.3 (m, 1H), 0.75 (m, 1H). MS (m/z): 487, 489 [MH]⁺. 92

n.d. NMR (¹H, CD₃OD): δ 7.54 (m, 3H), 7.29 (d, 2H), 7.23 (d, 1H), 4.12(dd, 1H), 3.88 (dd, 1H), 3.82 (s, 3H), 3.65 (m, 2H), 3.50 (t, 2H), 3.40(t, 2H), 2.3 (m, 3H), 1.50- 1.3 (2t, 2H). 93

2.42 NMR (¹H, DMSO): δ 10.45 (bs, HCl), 8.85 (dd, 1H), 8.75 (dd, 1H),8.1 (dt, 1H), 7.6 (dd, 1H), 7.45 (d, 2H), 7.1 (d, 2H), 4.0 (m, 2H), 3.6(m, 2H + water), 3.35 (m, 4H), 2.5 (m, 2H + DMSO), 2.2 (m, 3H), 1.6 (m,1H), 1.2 (t, 3H), 1.1 (m, 1H). MS (m/z): 484, 486 [MH]⁺. 94

3.02 NMR (¹H, DMSO): δ 10.45 (bs, HCl), 8.2 (d, 1H), 7.9 (d, 1H), 7.55(d, 2H), 7.25 (d, 2H), 4.05 (m, 1H), 3.7 (m, 1H), 3.5 (m, 1H + water),3.4 (s, 3H), 3.3 (m, 4H), 2.5 (s, 3H + DMSO), 2.2 (m, 3H), 1.6 (m, 1H),1.2 (m, 1H), 1.1 (m, 1H). MS (m/z): 552, 554 [MH]⁺. 95

n.d. NMR (¹H, DMSO): 10.6 (broad s, 1H, HCl), 7.65 (s, 1H), 7.5 (d, 2H),7.25 (d, 2H), 4.1 (s, 3H), 4.0 (m, 1H), 3.8 (s, 3H + water), 3.7 (m,1H), 3.5 (m, 2H), 3.25 (m, 4H), 2.2 (m, 3H), 1.65 (m, 1H), 1.1 (m, 1H)MS (m/z): 597, 599.

Example 963-(3-{[4-Methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-(1R,5R/1S,5S)-1-[5-(trifluoromethyl)-2-pyridinyl]-3-azabicyclo[3.1.0]hexanehydrochloride

The title compound was prepared in analogy to the method described inExample 1 as a white slightly hygroscopic solid (70 mg, 45%), from1-[5-(trifluoromethyl)-2-pyridinyl]-3-azabicyclo[3.1.0]hexane.

NMR (corresponding free base, ¹H, CD₃OD): δ 8.71 (s, 1H), 7.93 (s, 1H),7.78 (dd, 1H), 7.15 (d, 1H), 3.72 (s, 3H), 3.41 (d, 1H), 3.36 (t, 2H),3.13 (d, 1H), 2.8 (d, 1H), 2.68 (m, 2H), 2.54 (s, 3H), 2.48 (dd, 1H),2.04 (m, 3H), 1.6 (m, 1H), 1.26 (dd, 1H). MS (m/z): 465 [MH]⁺.

Example 96 was separated to give the separated enantiomers bysemi-preparative HPLC using a chiral column Chirapak AD-H 5 μm, 250×4.6mm, eluent A: n-hexane; B: Ethanol+0.1% isopropylamine, gradientisocratic 30% B v/v, flow rate 6 mL/min, detection UV at 270 nm.Retention times given were obtained using a chiral column Chirapak AD-H5 μm, 250×4.6 mm, eluent A: n-hexane; B: Ethanol, gradient isocratic 30%B v/v, flow rate 0.8 mL/min, detection UV at 200-400 nm.

Enantiomer 1 was recovered in 18 mg yield as a white solid,hydrochloride salt from the racemate (70 mg). Rt.=19.09 min. Purity 100%a/a by UV

Enantiomer 2 was recovered in 18 mg yield as white solid, hydrochloridesalt from the racemate (70 mg). Rt.=21.6 min. Purity 99% a/a by UV.

Enantiomer 2 showed fpKi (D3)>1 log-unit higher than Enantiomer 1.

Example 973-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-(1R,5R/1S,5S)-1-[6-(trifluoromethyl)-2-pyridinyl]-3-azabicyclo[3.1.0]hexanedihydrochloride

3-(Phenylmethyl)-1-[5-(trifluoromethyl)-2-pyridinyl]-3-azabicyclo[3.1.0]hexane(0.19 mmol) was dissolved in 1,2-dichloroethane (1 mL) and 1-chloroethylchloridocarbonate was added (0.21 mmol). After two microwave cycles (5min at 120° C. and 10 min at 140° C.) the solvent was removed at reducedpressure. Methanol (2 mL) was added and the solution was submitted to anadditional microwave cycle (10 min, 120° C.). The solvent was removed atreduced pressure to give 47 mg of intermediate which was used withoutfurther purification and treated in analogy to the method described inExample 1 to give the title compound (5 mg, 5%) as a white slightlyhygroscopic solid.

NMR (¹H, CD₃OD): δ 8.38 (s, 1H), 7.99 (dd, 1H), 7.67 (dd, 1H), 7.48 (dd,1H), 4.18 (d, 1H), 4.06 (d, 1H), 3.88 (d, 1H), 3.79 (s, 3H), 3.63 (dd,1H), 3.50 (m, 2H), 3.41 (t, 2H), 2.49 (m, 1H), 2.44 (s, 3H), 2.31 (m,2H), 1.69 (m, 1H), 1.65 (dd, 1H). MS (m/z): 465 [MH]⁺.

Example 98(1R,5S/1S,5R)-1-[3-Fluoro-4-(1H-pyrrol-1-ylmethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexanehydrochloride

The title compound was prepared in analogy to the method described inExample 1 as a white slightly hygroscopic solid (5.4 mg, yield=19%),from1-[3-fluoro-4-(1H-pyrrol-1-ylmethyl)phenyl]-3-azabicyclo[3.1.0]hexane(Preparation 57).

NMR (as formate salt) (1H, CDCl3): δ 7.9 (s, 1H), 6.8 (m, 4H), 6.65 (s,2H), 6.15 (s, 2H), 5.05 (s, 2H), 3.66 (s, 3H), 3.4 (d, 1H), 3.25 (t,2H), 3.2 (d, 1H), 2.75 (t, 2H), 2.6 (d, 1H), 2.55 (m, 1H), 2.5 (s, 3H),2.0 (m, 2H), 1.7 (m, 1H), 1.45 (t, 1H), 0.8 (m, 1H); acidic proton notobserved. MS (hydrochloride salt) (m/z): 475 [MH]⁺.

Examples 99-104

Examples 99-104 were prepared as white slightly hygroscopic solids from(1R,5S/1S,5R)-3-(3-chloropropyl)-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane(40 mg) in analogy to the method described for Examples 53-58.

Example Name and Structure R (min) Analytical data  99

5.82 MS (m/z): 477 [MH]⁺. 100

5.05 NMR (¹H, DMSO): δ 9.11 (d, 1H), 8.76 (dd, 1H), 8.73 (bs, 1H), 8.08(d, 1H), 8.01 (bdd, 1H), 7.83 (d, 1H), 4.25 (d, 1H), 3.95 (d, 1H), 3.81(s, 3H), 3.79 (d, 1H), 3.71 (dd, 1H), 3.54 (t, 2H), 3.45 (t, 2H), 2.89(s, 3H), 2.46 (m, 1H), 2.33 (m, 2H), 1.69 (dd, 1H), 1.47 (t, 1H). Acidicproton not observed. MS (m/z): 476 [MH]⁺. 101

4.82 MS (m/z): 476 [MH]⁺ 102

6.27 MS (m/z): 461 [MH]⁺ 103

5.40 MS (m/z): 496 [MH]⁺ 104

7.36 MS (m/z): 528 [MH]⁺.

Examples 105-109

Examples 105-109 were prepared as white slightly hygroscopic solids from5-[(1R,5S/1S,5R)-3-(3-chloropropyl)-3-azabicyclo[3.1.0]hex-1-yl]-2-methyl-1,3-benzothiazole(40 mg) in analogy to the method described in Example 53-58.

Example Name R (min) Analytical data 105

5.83 MS (m/z): 478 [MH]⁺. 106

5.04 MS (m/z): 477 [MH]⁺. 107

6.28 MS (m/z): 462 [MH]⁺ 108

5.35 MS (m/z): 497 [MH]⁺ 109

7.43 NMR (¹H, DMSO): δ 7.98-8.03 (m, 4H), 7.97 (d, 1H), 7.89 (s, 1H),7.45 (d, 1H), 4.2 (d, 1H), 3.91 (d, 1H), 3.78 (s, 3H), 3.73 (d, 2H),3.49 (m, 4H), 2.88 (s, 3H), 2.36 (m, 3H), 1.6 (t, 1H), 1.37 (t, 1H). MS(m/z): 530 [MH]⁺.

Example 110(1R,5S/1S,5R)-1-[3-Fluoro-5-(trifluoromethyl)phenyl]-3-(3-({[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-azabicyclo[3.1.0]hexanehydrochloride

The title compound was prepared in analogy to the method described inExample 1 in 383 mg yield as a white slightly hygroscopic solid (y=46%)from(1R,5S/1S,5R)-1-[3-fluoro-5-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane(400 mg).

NMR (¹H, CD3OD): δ 8.46 (s, 1H), 7.54 (bs, 1H), 7.47 (bd, 1H), 7.41 (bd,1H), 4.19 (d, 1H), 3.09 (d, 1H), 3.87 (s, 3H), 3.71 (m, 2H), 3.51 (t,2H), 3.46 (t, 2H), 2.49 (s, 3H), 2.33 (m, 3H), 1.67 (m, 1H), 1.39 (m,1H). MS (m/z): 482 [MH]⁺.

(1R,5S/1S,5R)-1-[3-Fluoro-5-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-azabicyclo[3.1.0]hexanehydrochloride was separated to give the separated enantiomers bysemipreparative Supercritical Fluid Chromatography (Gilson) using achiral column Chiralcel AD-H, 25×2.1 cm, eluent CO₂ containing 9%(ethanol+0.1% isopropylamine), flow rate 22 mL/min, P 192 bar, T 36° C.,detection UV at 220 nm, loop 2 mL. Retention times given were obtainedusing an analytical Supercritical Fluid Chromatography (Gilson) using achiral column Chiralpak AD-H, 25×0.46 cm, eluent CO₂ containing 10%(ethanol+0.1% isopropyilamine), flow rate 2.5 mL/min, P 180 bar, T 35°C., detection UV at 220 nm.

Enantiomer 1 was recovered in 19.4 mg yield as white solid,hydrochloride salt from the racemate (100 mg). Rt.=12.6 min. Purity >99%a/a by UV

Enantiomer 2 was recovered in 18.3 mg yield as white solid,hydrochloride salt from the racemate (100 mg). Rt.=14.7 min. Purity >99%a/a by UV

Enantiomer 1 showed fpKi (D3)>1 log-unit higher than Enantiomer 2.

Example 110(1R,5S/1S,5R)-1-[3-Fluoro-5-(trifluoromethyl)phenyl]-3-(3-({[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-azabicyclo[3.1.0]hexanehydrochloride

The title compound was prepared in analogy to the method described inExample 1 in 383 mg yield as a white slightly hygroscopic solid (y=46%)from(1R,5S/1S,5R)-1-[3-fluoro-5-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane(400 mg).

NMR (¹H, CD3OD): δ 8.46 (s, 1H), 7.54 (bs, 1H), 7.47 (bd, 1H), 7.41 (bd,1H), 4.19 (d, 1H), 3.09 (d, 1H), 3.87 (s, 3H), 3.71 (m, 2H), 3.51 (t,2H), 3.46 (t, 2H), 2.49 (s, 3H), 2.33 (m, 3H), 1.67 (m, 1H), 1.39 (m,1H). MS (m/z): 481 [MH]⁺.

(1R,5S/1S,5R)-1-[3-Fluoro-5-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-azabicyclo[3.1.0]hexanehydrochloride was separated to give the separated enantiomers bysemipreparative Supercritical Fluid Chromatography (Gilson) using achiral column Chiralcel AD-H, 25×2.1 cm, eluent CO2 containing 9%(ethanol+0.1% isopropylamine), flow rate 22 mL/min, P 192 bar, T 36° C.,detection UV at 220 nm, loop 2 mL. Retention times given were obtainedusing an analytical Supercritical Fluid Chromatography (Gilson) using achiral column Chiralpak AD-H, 25×0.46 cm, eluent CO2 containing 10%(ethanol+0.1% isopropyilamine), flow rate 2.5 mL/min, P 180 bar, T 35°C., detection UV at 220 nm.

Enantiomer 1 was recovered in 19.4 mg yield as white solid,hydrochloride salt from the racemate (100 mg). Rt.=12.6 min. Purity >99%a/a by UV

Enantiomer 2 was recovered in 18.3 mg yield as white solid,hydrochloride salt from the racemate (100 mg). Rt.=14.7 min. Purity >99%a/a by UV

Enantiomer 1 showed fpKi (D3)>1 log-unit higher than Enantiomer 2.

Example 111(1R,5S/1S,5R)-1-[2-Fluoro-3-(trifluoromethyl)phenyl]-3-(3-({[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-azabicyclo[3.1.0]hexanehydrochloride

The title compound was prepared in analogy to the method described inExample 1 in 349 mg yield as a white slightly hygroscopic solid (y=45%)from(1R,5S/1S,5R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane(400 mg).

NMR (¹H, CD3OD): δ 8.46 (s, 1H), 7.75-7.65 (m, 2H), 7.38 (t, 1H), 4.1(d, 1H), 3.93 (d, 1H), 3.78 (s, 3H), 3.71 (d, 1H), 3.54 (d, 1H), 3.48(t, 2H), 3.38 (t, 2H), 2.45 (s, 3H), 2.36 (m, 1H), 2.25 (m, 2H), 1.54(m, 1H), 1.34 (m, 1H). MS (m/z): 481 [MH]⁺.

(1R,5S/1S,5R)-1-[2-Fluoro-3-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-azabicyclo[3.1.0]hexanehydrochloride was separated to give the separated enantiomers bysemipreparative Supercritical Fluid Chromatography (Gilson) using achiral column Chiralpak AD-H, 250×4.6 mm, eluent n-Hexane/Ethanol 88/12(isocratic), flow rate 1 mL/min, P 200-400 bar, T 36° C., detection UVat 200-400 nm, loop 2 mL. Retention times given were obtained using ananalytical Supercritical Fluid Chromatography (Gilson) using a chiralcolumn Chiralpak AD-H, 250×4.6 mm, eluent n-Hexane/Ethanol 88/12(isocratic), flow rate 1 mL/min, P 200-400 bar, T 36° C., detection UVat 200-400 nm.

Enantiomer 1 was recovered in 37 mg yield as white solid, hydrochloridesalt from the racemate (98 mg). Rt.=20.4 min. Purity 98.5% a/a by UV

Enantiomer 2 was recovered in 35 mg yield as white solid, hydrochloridesalt from the racemate (98 mg). Rt.=23.0 min. Purity 99.5% a/a by UV

Enantiomer 2 showed fpKi (D3)>1 log-unit higher than Enantiomer 1.

Example 112(1R,5S/1S,5R)-1-[4-(Methyloxy)-5-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-azabicyclo[3.1.0]hexanehydrochloride

The title compound was prepared in analogy to the method described inExample 1 in 658 mg yield as a white slightly hygroscopic solid (y=76%)from(1R,5S/1S,5R)-1-[4-(methyloxy)-5-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane(430 mg).

NMR (¹H, CD3OD): δ 8.37 (s, 1H), 7.57 (m, 2H), 7.17 (d, 1H) 3.9 (m, 4H),3.77 (s, 3H), 3.74 (m, 1H), 3.65-3.30 (m, 6H), 2.44 (s, 3H), 2.21 (m,2H), 2.13 (m, 1H), 1.43 (t, 1H), 1.24 (m, 1H). MS (m/z): 494 [MH]⁺.

(1R,5S/1S,5R)-1-[4-(Methyloxy)-5-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-azabicyclo[3.1.0]hexanehydrochloride was separated to give the separated enantiomers bysemipreparative Supercritical Fluid Chromatography (Gilson) using achiral column Chiralpak AD-H, 250×4.6 mm, eluent n-Hexane/Ethanol+0.1%isopropylamine 70/30 (isocratic), flow rate 6 mL/min, detection UV at270 nm, loop 2 mL. Retention times given were obtained using ananalytical Supercritical Fluid Chromatography (Gilson) using a chiralcolumn Chiralpak AD-H, 250×4.6 mm, eluent n-Hexane/Ethanol 70/30(isocratic), flow rate 0.8 mL/min, detection UV at 200-400 nm.

Enantiomer 1 was recovered in 18.3 mg yield as white solid,hydrochloride salt from the racemate (100 mg). Rt.=15.5 min. Purity >99%a/a by UV

Enantiomer 2 was recovered in 22.2 mg yield as white solid,hydrochloride salt from the racemate (100 mg). Rt.=17.5 min. Purity >99%a/a by UV

Enantiomer 2 showed fpKi (D3)>2 log-units higher than Enantiomer 1.

Example 113(1R,5S/1S,5R)-1-[4-(4-Chloro-2-fluorophenyl]-3-(3-({[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-azabicyclo[3.1.0]hexanehydrochloride

The title compound was prepared in analogy to the method described inExample 1 in 112 mg yield as a white slightly hygroscopic solid from(1R,5S/1S,5R)-1-[4-chloro-2-fluorophenyl]-3-azabicyclo[3.1.0]hexane (130mg).

NMR (¹H, CD3OD): δ 8.27 (s, 1H), 7.3 (t, 1H), 7.1 (m, 2H), 3.95 (d, 1H),3.8 (d, 1H), 3.67 (s, 3H), 3.56 (dd, 1H), 3.4-3.2 (m, 5H), 2.34 (s, 3H),2.15 (m, 3H), 1.4 (t, 1H), 1.18 (t, 1H). MS (m/z): 448 [MH]⁺.

Example 114(1R,5S/1S,5R)-1-[3-(2-{[4-Methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-{3-[(trifluoromethyl)oxy]phenyl}-3-azabicyclo[3.1.0]hexanehydrochloride

The title compound was prepared in analogy to the method described inExample 1 in 160 mg yield as a white slightly hygroscopic solid from1-{3-[(trifluoromethyl)oxy]phenyl}-3-azabicyclo[3.1.0]hexane (150 mg).

NMR (¹H, CD3OD): δ 8.41 (s, 1H), 7.49 (t, 1H), 7.3 (s, 1H), 7.37 (d,1H), 7.24 (m, 1H), 4.17 (d, 1H), 3.9 (d, 1H), 3.8 (s, 3H), 3.69 (d, 2H),3.51 (t, 2H), 3.42 (t, 2H), 2.47 (s, 3H), 2.3 (m, 3H), 1.57 (dd, 1H),1.36 (t, 1H). MS (m/z): 480 [MH]⁺.

Example 115(1R,5S/1S,5R)-1-(2-fluoro-4-methylphenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexanehydrochloride

The title compound was prepared in analogy to the method described inExample 1 in 60 mg yield as a white slightly hygroscopic solid from1-(2-fluoro-4-methylphenyl)-3-azabicyclo[3.1.0]hexane (148 mg).

NMR (¹H, CD3OD): δ 8.39 (s, 1H), 7.26 (t, 1H), 7.01 (m, 2H), 3.93 (m,1H), 3.77 (m, 4H), 3.61 (m, 1H), 3.41-3.38 (m, 5H), 2.47 (s, 3H), 2.36(s, 3H), 2.23 (m, 2H), 2.19 (m, 1H), 1.45 (t, 1H), 1.21 (t, 1H). MS(m/z): 428 [MH]⁺.

Example 116(1R,5S/1S,5R)-1-[3-Chloro-4-(methyloxy)phenyl]-3-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexanehydrochloride

The title compound was prepared in analogy to the method described inExample 1 in 56 mg yield as a white slightly hygroscopic solid from1-[3-chloro-4-(methyloxy)phenyl]-3-azabicyclo[3.1.0]hexane (60 mg).

NMR (¹H, CD3OD): δ 8.4 (s, 1H), 7.35 (m, 1H), 7.1 (m, 2H), 4.01 (m, 1H),3.89 (m, 4H), 3.8 (s, 3H), 3.6-3.3 (m, 6H), 2.47 (s, 3H), 2.23 (m, 2H),2.19 (m, 1H), 1.4 (m, 1H), 1.2 (m, 1H). MS (m/z): 460 [MH]⁺.

Example 117(1R,5S/1S,5R)-1-[4-(2,4-Dimethyl-1,3-thiazol-5-yl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexanehydrochloride

A mixture of(1R,5S/1S,5R)-1-[4-(2,4-dimethyl-1,3-thiazol-5-yl)phenyl]-3-aza-bicyclo[3.1.0]hexane(70 mg),3-[(3-chloropropyl)thio]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole(85 mg), potassium carbonate (43 mg), Na₂CO₃ and sodium iodide (45 mg)in anhydrous DMF (0.6 mL) was heated at 60° C. for 24 h. Afterelimination of the solvent in vacuo the residue was dissolved in ethylacetate and the organic phase was washed with saturated aqueous sodiumbicarbonate, dried over sodium sulphate and concentrated in vacuo. Thecrude was purified by flash chromatography (dichloromethane to 10% MeOHin dichloromethane) to give 65 mg of the free base of the titlecompound. To a solution of this material in dichloromethane (1 mL) wasadded HCl (1 M in Et₂O, 0.13 mL), the solvent evaporated under vacuo andthe material thus obtained triturated with Et₂O to give 69 mg of thetitle compound as a white solid (50% yield).

NMR (¹H, DMSO): δ 10.39 (bs, 1H), 8.56 (s, 1H), 7.39 (d, 2H), 7.35 (d,2H), 4.02 (m, 1H), 3.72 (m, 1H), 3.68 (s, 3H), 3.60 (t, 1H), 3.51 (bm,1H), 3.27 (m, 4H), 2.60 (s, 3H), 2.37 (s, 3H), 2.35 (s, 3H), 2.19 (m,1H), 2.16 (m, 2H), 1.62 (m, 1H), 1.15 (m, 1H); MS (m/z): 507.2 [MH]⁺.

Example 118(1R,5S/1S,5R)-3-(3-{[4-Methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-{4-[6-(trifluoromethyl)-2-pyridinyl]phenyl}-3-azabicyclo[3.1.0]hexanehydrochloride

The title compound was prepared in analogy to the method described inExample 117 (using(1R,5S/1S,5R)-1-{4-[6-(trifluoromethyl)-2-pyridinyl]phenyl}-3-azabicyclo[3.1.0]-hexane)in 55% yield as a white solid.

NMR (¹H, CDCl₃): δ 10.44 (bs, 1H), 8.56 (s, 1H), 8.29 (d, 1H), 8.17 (t,1H), 8.09 (d, 2H), 7.84 (d, 1H), 7.43 (d, 2H), 4.08 (m, 1H), 3.75 (m,1H), 3.68 (s, 3H), 3.64 (t, 1H), 3.53 (bm, 1H), 3.28 (m, 4H), 2.37 (s,3H), 2.27 (m, 1H), 2.17 (m, 2H), 1.68 (m, 1H), 1.17 (m, 1H); MS (m/z):541.2 [MH]⁺.

Example 119(1R,5S/1S,5R)-1-[3-(2,4-Dimethyl-1,3-thiazol-5-yl)phenyl]-3-(3-({[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexanehydrochloride

The title compound was prepared in analogy to the method described inExample 117 (using(1R,5S/1S,5R)-1-[3-(2,4-dimethyl-1,3-thiazol-5-yl)phenyl]-3-azabicyclo[3.1.0]-hexane)in 53% yield as a white solid.

NMR (¹H, CDCl₃): δ 10.53 (b, 1H), 8.58 (s, 1H), 7.43 (d, 1H), 7.28-7.38(m, 3H), 4.07 (dd, 1H), 3.73 (dd, 1H), 3.70 (s, 3H), 3.61 (t, 1H), 3.53(m, 1H), 3.34 (m, 2H), 3.29 (t, 2H), 2.64 (s, 3H), 2.39 (s, 3H), 2.73(s, 3H), 2.23 (m, 1H), 2.20 (m, 2H), 1.68 (t, 1H), 1.16 (t, 1H); MS(m/z): 507.1 [MH]⁺.

Example 120(1R,5S/1S,5R)-3-(3-{[4-Methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[3-(5-methyl-2-thienyl)phenyl]-3-azabicyclo[3.1.0]hexanehydrochloride

The title compound was prepared in analogy to the method described inExample 117 (using(1R,5S/1S,5R)-1-[3-(5-methyl-2-thienyl)phenyl]-3-azabicyclo[3.1.0]hexane)in 51% yield as a white solid.

NMR (¹H, CDCl₃): δ 10.44 (b, 1H), 8.58 (s, 1H), 7.49 (d, 1H), 7.45 (dt,1H), 7.37 (t, 2H), 7.18 (dt, 1H), 6.84 (t, 1H), 4.08 (dd, 1H), 3.76 (dd,1H), 3.70 (s, 3H), 3.62 (t, 1H), 3.54 (tm, 1H), 3.28 (t, 4H), 2.48 (s,3H), 2.39 (s, 3H), 2.24 (m, 1H), 2.19 (t, 2H), 1.65 (t, 1H), 1.16 (t,1H); MS (m/z): 472.0 [MH]⁺.

Example 121(1R,5S/1S,5R)-1-[4-(3,5-Dimethyl-4-isoxazolyl)phenyl]-3-(3-({[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane

The title compound was prepared in analogy to the method described inExample 117 (using(1R,5S/1S,5R)-1-[4-(3,5-dimethyl-4-isoxazolyl)phenyl]-3-azabicyclo[3.1.0]hexane),in 55% yield as a white solid.

MS (m/z): 491.2 [MH]⁺.

Example 122(1S,5R)-3-(3-{[5-(2,4-Dimethyl-1,3-oxazol-5-yl)-4-methyl-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]-hexanehydrochloride

A mixture of(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane(Preparation 18, 60 mg),3-[(3-chloropropyl)thio]-5-(2,4-dimethyl-1,3-oxazol-5-yl)-4-methyl-4H-1,2,4-triazole(Preparation 78, 78 mg),2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diaza-phosphorineon polystyrene (2.2 mmol/g, 140 mg) and a catalytic amount of NaI inacetonitrile dry (3 ml) was heated at 70° C. for 4 h, then overnight at55° C. The resin was removed by filtration and washed with acetonitrile(2×3 ml). The solvent was removed under vacuum, the remaining soliddissolved in DMF dry (0.5 ml),3-[(3-chloropropyl)thio]-5-(2,4-dimethyl-1,3-oxazol-5-yl)-4-methyl-4H-1,2,4-triazole(Preparation 78, 60 mg) was added followed by potassium carbonate (118mg). The resulting suspension was heated at 60° C. overnight. At roomtemperature a saturated solution of sodium bicarbonate was added (4 ml)and the suspension was extracted with DCM (2×6 ml). The resultingsolution was charged onto a SCX column and eluted with MeOH followed byMeOH/NH₃ 0.25 M. The resulting material was purified by preparative HPLCand then converted to the hydrochloride salt following the methoddescribed for Example 15 to give the title compound as a white slightlyhygroscopic solid (37 mg, 27% yield).

NMR (¹H, DMSO): δ 10.38 (b, 1H), 7.71 (d, 1H), 7.64 (t, 1H), 7.59 (d,1H), 3.98 (bd, 1H), 3.76 (bd, 1H), 3.65 (s, 3H), 3.54 (b, 1H), 3.44 (bt,1H), 3.31 (b, 2H), 3.24 (t, 2H), 2.47 (s, 3H), 2.35 (m, 1H), 2.29 (s,3H), 2.11 (m, 2H), 1.63 (t, 1H), 1.13 (t, 1H). MS (m/z): 496 [MH]⁺.

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

It is to be understood that the present invention covers allcombinations of particular groups described herein above.

The application of which this description and claims forms part may beused as a basis for priority in respect of any subsequent application.The claims of such subsequent application may be directed to any featureor combination of features described herein. They may take the form ofproduct, composition, process, or use claims and may include, by way ofexample and without limitation, the following claims:

1-57. (canceled)
 58. A composition of matter comprising3-(3-{[4-methyl-5-(4-pyridazinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane,a stereoisomer thereof, or a salt thereof.
 59. A composition of matteraccording to claim 35 comprising(1S,5R)-3-(3-{[4-Methyl-5-(4-pyridazinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[4-(trifluoromethyl)-phenyl]-3-azabicyclo[3.1.0]hexaneor a pharmaceutically acceptable salt thereof and(1S,5R)-3-(3-{[4-Methyl-5-(4-pyridazinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexanehydrochloride.
 60. A composition of matter according to claim 35comprising(1S,5R)-3-(3-{[4-methyl-5-(4-pyridazinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[4-(trifluoromethyl)-phenyl]-3-azabicyclo[3.1.0]hexane.
 61. A composition of matter according to claim 35comprising(1S,5R)-3-(3-{[4-methyl-5-(4-pyridazinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[4-(trifluoromethyl)-phenyl]-3-azabicyclo[3.1.0]hexanehydrochloride.
 62. A method of treating substance abuse comprisingadministering an effective amount of3-(3-{[4-methyl-5-(4-pyridazinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane,or(1S,5R)-3-(3-{[4-methyl-5-(4-pyridazinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[4-(trifluoromethyl)-phenyl]-3-azabicyclo[3.1.0]hexane,or a mixture of3-(3-{[4-methyl-5-(4-pyridazinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane, or (1S,5R)-3-(3-{[4-methyl-5-(4-pyridazinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[4-(trifluoromethyl)-phenyl]-3-azabicyclo[3.1.0]hexane, neat or admixed with a pharmaceutically acceptablecarrier.
 63. A pharmaceutical composition comprising3-(3-{[4-methyl-5-(4-pyridazinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane,or (1S,5R)-3-(3-{[4-methyl-5-(4-pyridazinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[4-(trifluoromethyl)-phenyl]-3-azabicyclo[3.1.0]hexane,or a mixture of3-(3-{[4-methyl-5-(4-pyridazinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane, or (1S,5R)-3-(3-{[4-methyl-5-(4-pyridazinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-[4-(trifluoromethyl)-phenyl]-3-azabicyclo[3.1.0]hexane,or a pharmaceutically acceptable salt thereof; and a pharmaceuticallyacceptable carrier.